Initial Quality Assessment
`Branch I
`Division of New Drug Quality Assessment I
`
`OND Division: Division of Neurology Products
`NDA: 204-063
`Applicant: Biogen Idee Inc.
`Stamp Date: 27-Feb-2012
`PDUFA Date:
`ll~ is proposed
`Trademark:
`Estnblished Nnme: Dimethyl fi.unarate [USAN 2005]
`Dosage Form: Capsule, delayed release
`Route of Administration: Oral
`Indication: Treatment of relapsing forms of multiple sclerosis
`CMC Lead : Martha R. Heimann, Ph.D.
`Yes No
`[81 D
`[8] 0
`
`ONDQA F ileability:
`Comments fm· 74-D ay Letter
`
`Summary and Critical Issues:
`Summary
`
`Dimethyl fi.1marate (BGQ0012) has been developed by Biogen-Idec as a novel treatment for
`relapsing fotms of multiple sclerosis (MS). The pharmacological properties ofBGQ0012 appear
`to be predominately mediated through activation of the nuclear factor (erythroid-derived 2)-like
`2 (NFE2L2 or Nrf2) antioxidant response pathway, which is the primruy cellular defense system
`for responding to a variety of potentially toxic stimuli.
`
`The cnnent NDA rovides for a delayed release dimethyl fi.nnarate capsule fotmulation
`·n~ . Two strengths are proposed, 120 mg and 240 mg. The
`pro uct IS rnten e for use rn tlie treatment of J>atients with relapsing fotms of multiple sclerosis
`~~
`(6)(4)
`The recommended starting dose is 120 mg taken twice daily for seven days, followeJ
`by increase to the target dose of240 mg taken twice daily.
`
`Prior to submission of the NDA the applicant sought Agency feedback dllling a Type C CMC(cid:173)
`only meeting held on 21-Jul-2011. Minutes for the meeting can be found in DARRTS.
`Additionally, the briefing package for the meeting, submitted on 20-Jllll-2011 to IND 73,061, is
`available in the EDR. Key issues addressed dm·ing the meeting are stUlllllarized below.
`
`• Based on infotmation provided in the briefing package, the Agency agreed to designation
`(b~ as the regulatory starting material.
`of
`
`dming manufacture ofthe
`• There is a potential for fotmation of
`(l;i 141 in the drug product
`drug substance. The applicant proposed not mcluding a test for
`specification based on kinetic modeling and spiking experiments. The Agency initially
`
`Reference 10: 3101584
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`Page 1 of17
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`Biogeo Exhibit 2373
`Coalition v. Biogeo
`IPR2015-01993
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`

`

`NDA 204-063 Initial Quality Assessment
`
`Page 2
`
`recommended that the applicant continue testing
`commercial batches before requesting deletion ofl--t:;-h-e":"te-s~t fi:om the specification. During
`the meeting, however, the Agency agreed that the finn could present the rationale for
`deleting the specification, and additional supporting data not included in the briefing
`package, in the NDA filing for review.
`
`• The applicant proposed that no d.mg substance or drug product manufacturing process
`parameters be designated as critical. The finn was advised to submit the development
`reports that included the rationale why there are no critical process parameters, including
`parameters that were not studied.
`
`• The applicant requested concun:ence with the proposed dissolution method and was
`advised to submit a full method development report before a decision could be made. It
`is noted that there were several communications after the meeting but the Agency has not
`yet concun ed with the proposed method.
`
`• The Agency agreed that the proposed chaJacterization testing to qualify the higher
`st1ength (240 mg capsule) would be adequate provided the applicant conduct the
`proposed b ioequivalence study. With respect to the proposed stability package for the
`higher strength, the finn was advised that the expiration dating period assigned would be
`limited based on the stability data to be provided in the NDA, i.e., 3 months at
`submission and 6 mon ths update dming the review cycle.
`
`Drug Substance
`
`The active ingredient, dimethyl fumarate [systematic name: (E)-2-butenedioic acid dimethyl
`ester], is a neutral small molecule with m olecular fonnula C&Hs04 and molecular wei@.44.l3.
`The dm~ substance is sli~y soluble in water 2.84 mg/mL) and aqueous buffers.
`~><•>
`The aeplicant indicates that dimeth~l
`OT<Il
`fumarate should be classified as BCS Class I.
`The d.mg_, substance is._n_o":"t ,_y_gr-·o_s_c-op- t .• c-; 'h'~-ow_e_v-er-·, i·fis repOlted to be
`..._ ________________________ ~
`4 The chemical stmctme of dimethyl fumarate is:
`I6JT
`
`0
`
`H
`
`\
`
`H
`
`The bulk dru substance is manufacntred r - - - - - - - - - - - - - - - - - - ,(bJ<4J
`
`'I' All infOlmation regarding manufacturing and
`.... ce is provided in the NDA itself; no DMFs are referenced. It
`,_ch'_a_t-·a-ct-:-e-n.,...z -a"!"'ti_o_n_o'"l'f:-:-th;-e--;dt-1-lg- su-;b-s-:-tan
`is noted that although two separate 3.2.S modules are provided for the two suppliers, the
`
`Reference ID: 3101584
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`Page 2 of 17
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`

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`NDA 204-063 Initial Quality Assessment
`
`Page 3
`
`information provided in both modules is virtually identical. The following differences were
`noted during the initial assessment.
`• Commercial batch scale will
`[Module 3.2.S.2.2]
`
`(b) (4)
`
`.
`
`•
`
`• Different control strategies will be used during manufacture at the two sites.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`• Although the same analytical procedures are used by both manufacturers; separate
`methods validation reports for drug substance assay/related substances (HPLC) and
`residual solvents (GC) are provided. [Modules 3.2.S.4.3 and 3.2.R]
`• Batch analysis data provided in Module 3.2.S.4.4 are specific to each manufacturer.
`
`The proposed drug substance specification is given in applicant's Table 1 [Module 3.2.S.4.1],
`which is reproduced in the following page.
`
`Reference ID: 3101584
`
`Page 3 of 17
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`

`NDA 204-063 Initial Quality Assessment
`
`Page 4
`
`Table 1:
`
`i\ttribu u
`
`Dcscnption 1
`
`Identification:
`
`Release Specificatioa for Drug Substance
`
`Test
`
`Visual inspection
`
`())(4)
`
`Jdcotifacation A
`
`Jdcntdio3lion B
`
`HPLC'
`
`IR
`
`HPLC
`
`Retention tunc of the sample p;:ak
`corre~pnn<N to the rett:ntion lime
`of the: rcfcronc:e standard
`JR spectrum of tho &3mplc
`ccmc>.prmck to the IR 'pec1mm of
`the reference standard
`
`(4
`
`IDI\4)
`
`The specification for dimethyl fumarate includes test parameters that are ~')pica ! for ,a small
`molecule. Assay and Related Substances are detenn ined by a
`!bH HPLC
`method usi ng 1m acetonibile/0.1% aqueous phosphoric acid mobile ph11se 11nd UV detection at
`210 um. There are two specified impurities,
`llll
`41
`. As noted above, the applicant proposes to exclnde'-__ •DH
`from the specification. The justificAtion provtoedis based
`on the cbemJstry of the synth.-e-s'is""-, 'kin~ etic modeling experiments, spiking studies, and batch
`analyses.
`
`The drug substance prima1y stability package includes long-tenn (25°C/60% R. H .) and
`intetmediate data (30°C/65% R. H.) through 60 months and accelerated data (40°C/75% R. H .)
`~ . Six
`through six months for three commercial scale batches manufactured
`IIIH• ; however,
`months of data are provided for three commercial scale batcbes manu factured
`for
`!D)f• batches only samples stored the intermediate and accelerated conditions were tested.
`~~~~~ retest date is proposed.
`Additional supportive data are also provided. A
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`Reference ID: 3101584
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`NDA 204-063 Initial Quality Assessment
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`Page 5
`
`Drug Product
`
`~posed dosao-e form is a delayed release capsule consisting of size 0 hard gelatin capsules
`L
`(b)\,ll Two capsule strengths are proposed. The 120 mg
`capsules have a white body with greeiL (41; 240 mg capsules have a green bodyj
`<bf(•'. Both
`strengths will be rinted with a roduct iaentifier (not specified in the applicatio'ii)~the
`compositions
`!till presented in Module 3.2.P.l are summarized in Table 2 below.
`
`Table 2: Theo retical Composition of Dimethy l Fumarate !
`
`lOJ(~
`
`Component
`
`l
`~ Ingredient
`
`oo•rm·~~ ""'"""'
`
`Croscarmellose sodium
`Microcrystalline cellulose
`(lj)lll}
`
`l
`
`~ Function
`j Active ingredient
`
`! Amountpercaesule (mg_) ____
`I
`j"
`120 m g
`240 mg
`240.0
`120.0
`~
`~
`
`!till~ I
`
`!till~) -
`
`!6JT4l:
`
`Silicified microcrystalline
`cellulose I
`Magnesium stearate 1
`Talc
`Colloidal silicon dioxide
`Subtotal
`Methacrylic acid copolymer, Type
`A 2
`
`' ltiJT(f
`
`Methacrylic acid copolymer
`dispersion (includes Sodium
`lauryl sulfate, Polysorbate 80) 2
`T riethyl citrate
`!tiJT4}
`!I
`Simethicone
`
`!
`
`TOTAL
`
`~
`
`{61l
`
`r--------------------------------------------------------------------------nij~
`
`(b)(~
`
`Reference ID: 3101584
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`Page 5 of 17
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`NDA 204-063 Initial Quality Assessment
`
`Page 6
`
`(ljTi are proportional. The finished 120 m c~~sules contain
`lb ~' •
`: 240 mg capsules contain
`lb
`
`The formulation and manufacturing process development history for Dimethyl Fumarate
`Capsules are presented as narratives in the Pharmaceutical Develo.J2!!lent Section; however,
`r~
`limited data are rovided. Note that the manufacturinR rocess
`
`lb><•>. It is recommended that tbe applicant' s explanation for the
`difference, and supporting data, be evaluated carefully.
`
`.---..... -.---:-~
`
`The applicant does not include detailed information for investigational formulations; however it
`is noted that the 120 mg capsules used in clinical trials and primary stability batches were blue(cid:173)
`white capsules rather than the proposed green-white. Additional information will be requested.
`
`Dimethyl Fumarate Capsules will be manufachU"ed
`
`"'"'~The manufacturing process development report
`:-!'" ___ _,
`presents a h·adtbona approach to process development. Limited data are provided to support the
`selected process parameters and operating ranges.
`
`Reference ID: 3101584
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`Page 6 of 17
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`

`NDA 204-063 Initial Quality Assessment
`
`Page 7
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`The proposed specifications for Dimeth 1 Fumarate Ca sules are summarized in Table 3. The
`b lbT<] are both specified
`dntg substance process impurities,
`as potential degradation products, with Illgher lunits than for the dmg su stance.
`
`Table 3: Specifications for Dimethyl Fumarate Capsules
`I r est
`I
`'
`
`120mg
`
`Acceptanc! .. ~!lte.'!_~- ---·-----·-- ----- --
`240mg
`
`(b)(4)'
`
`Attributes
`
`Description
`
`I
`
`Capsule
`
`: Visual Inspection
`
`IDI(4
`
`Visual Inspection
`
`Retention time of the sample peak corresponds to the retention time
`I
`of the reference standard
`UV spectrum of the sample peak corresponds to the UV spectrum of
`the reference standard
`
`· ui'fl'll
`
`- -
`
`HPLC
`
`uv
`HPLC
`,....----"-
`
`HPLC
`
`...._
`
`GC
`.-
`USP <905>,
`Ph. Eur. 2.9.40
`USP <711>.
`Ph. Eur. 2.9.3
`Karl Fischer
`
`Analytical procedures are straightforward. Assay, and Content Uniformity are detennined using
`the reverse phase HPLC [Cl8 column, pH 3.15 phosphate buffer- methanol 50:50 mobile phase
`and UV-PDA detection at 223 lllll]. A related HPLC method using a 60:40 buffer-methanol
`mobile phase is used for determination of impurities. Dissolution is detennined using USP
`Apparatus 2 at 100 rpm with 0.1 N HCl as the acid stage and pH 6. 8 phosphate buffer as the
`buffer stage. Dissolution is quantitated by HPLC; the conditions are stated to be similar to the
`Assay conditions. With respect to methods validation, only SUllllllary data is provided in Module
`3.2.P.5.5; the methods validation repotts are provided in Module 3.2.R.
`
`Dimethyl Fumarate Capsules will be £ackaged in HDPE bottles with aluminum foil induction .
`C<ll: closure and cotton filled
`seal, white polypropylene
`(bH4l
`,uJl.il~
`Module 3.2.P.7 contains iiil0iiiiiii10n regarding four sizes ofHDPEoottles
`however the details of the proposed colillllercial presentations (capsule stTength,
`and bottle size) are not provided.
`
`The NDA stability package is summarized in Tables 4 and 5. The applicant proposes ~
`expi..ty for both strengths in
`(6)l HDPE bottles.
`
`ID'f•j
`
`Reference ID: 3101584
`
`Page 7 of 17
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`

`NDA 204-063 Initial Quality Assessment
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`Page 8
`
`(ti) (4
`
`Table 4: Summary of Dimethyl Fumarate Capsule Batches Packaged in HOPE Bottles
`! Data Available
`i (Months)
`
`Batch Type
`
`; Capsule
`, Strength
`
`Primary
`Validation
`
`'
`! 120 mg
`~
`r ·····-·······-
`
`! 240 mg
`~
`
`· Capsule
`, Color
`!
`
`i
`l Blue-white
`~ ..
`
`Batch
`, Numbers
`!
`! 27664
`j 27666
`!
`(D)(4
`
`56060
`56061
`56062
`
`Not described in
`NDA
`
`[ Capsule Count/ : Storage
`, Bottle Size
`: Condition
`l 25°C/60% R. H.
`! 48
`l 3o•c JG5% R. H.
`i 48
`! 4o·c n 5% R. H. Is
`Not described in 3o•c JG5% R. H.
`0
`4o·cn5% R. H.
`0
`NDA
`
`l 14/60 cc
`i
`l 412/801/23025cc
`!
`L
`cc
`! 14tso cc
`~
`l Green-white
`! 4o· cns% R. H.
`1120/215 cc
`i
`i
`~~a.~~~~-== -- -· J
`: 42/120 cc
`r·--................... .__ -----~!-54-1 -64---;i-1416a-~~--- -· -·-·· -·--·-l·-·---·--·------------'------·----·- ·-
`120/215 cc
`!
`! 30•c JGS% R. H.
`i 240 mg
`! 3
`! 60/120 cc
`! 54165
`'
`! 54166
`i 90/215 cc
`£ 4o· cns% R. H.
`13
`~---------._-----.~n~~------~------~----------~----------~--------~
`I
`
`!
`}
`! 120 mg
`
`Registration
`
`! 47823
`·
`! 47824
`
`L__
`; 47825
`
`l 3o•c JG5% R. H.
`
`With respect to the stability data and proposed expiry the following key points are noted.
`
`MT•J
`• The rin9>al de~dation pathway for dimethyl fu~narate is
`~><41 HDPE bottles and
`m
`..,.is_l,.ik''e-;l-y-:-to--.b-e~th'_e_s-:t-ab"i"'li~ty-1"'irm---...t:""in-g--;:-fa-c~to-r-. -:;T"'h_e_a ...... pplicant has provided the results of
`
`Reference ID: 3101584
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`Page 8 of 17
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`

`NDA 204-063 Initial Quality Assessment
`
` 120 mg capsules as graphical presentations; it is
`regression analyses for
`(b) (4)
`recommended that detailed information be requested.
`
`Page 9
`
`(b) (4)
`
`• With respect to 120 mg capsules packaged in HDPE bottles, additional information is
`needed to determine whether the data provided would support the proposed expiry. For
`the registration batches, the applicant used a bracketing approach based on bottle fill and
`container size; however no information (e.g., headspace, surface to volume) to
`demonstrate that the chosen configurations studied are relevant to the commercial
`package configurations was provided. The Agency was not consulted prior to initiation
`of the bracketing stability protocol. It is also not clear whether the data from the primary
`validation batches would support assignment of a shelf life; only two batches were placed
`on stability and details of the package configurations were not provided.
`• Stability data for 240 mg capsules in
` HDPE bottles are limited to 3 months for
`(b) (4)
`all storage conditions. The applicant proposes the same expiry
` for 240 mg
`(b) (4)
`capsules based on comparability of the 240 mg formulation to the 120 mg formulation.
`As summarized in Table 2 above, however, the formulations are qualitatively and
`quantitatively different. The firm was advised during the pre-NDA meeting that the
`assigned expiry would be limited based on the stability data provided.
`Critical issues for review
`
`Drug Substance
`
` and the
`The equivalence of drug substance sourced
`(b) (4)
`corresponding manufacturing processes, should be evaluated carefully. The process descriptions
`given in Module 3.2.S.2.2 for the two sites are similar; but sketchy. It is recommended that the
`reviewer refer to the master batch record from each site (provided in Module 3.2.R) to evaluate
`the similarity of the processes.
`
` in the final drug substance specification
`The applicant’s justification for not testing for
`(b) (4)
`should be evaluated carefully based on the data provided for full scale production batches. The
`applicant will be asked to provide the method for determination
`, plus
`(b) (4)
`supporting validation data for review.
`
`Drug Product
`
`Critical issues are discussed in the summary above. A number of deficiencies are identified and
`should be communicated to the applicant.
`
`Reference ID: 3101584
`
`Page 9 of 17
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`

`

`NDA 204-063 Initial Quality Assessment
`
`Page 10
`
`Additional issues
`
`Environmental Assessment: The firm has submitted a claim for categorical exclusion under 21
`CFR 25.31(b) which states that the estimated concentration of the active moiety at the point of
`entry into the aquatic environment will be below one part per billion (1 ppb).
`
`Establishment Evaluation: A full list of facilities involved in the manufacture, packaging and
`testing of dimethyl fumarate and Dimethyl Fumarate Delayed Release Capsules is provided in
`the submission. Facilities requiring compliance evaluation were submitted in EES on
`08-Mar-2012.
`
`Labeling/Established Name: The active ingredient, dimethyl fumarate, is a neutral molecule.
`Therefore there are no issues of consistency between the established name “dimethyl fumarate
`delayed release capsules” and the labeled potency.
`
`Methods Validation--The drug substance is a new molecular entity; therefore, methods validation
`studies by the DPA St. Louis laboratory should be requested if the application is filed. It is
`recommended that the drug product assay and related substances methods be validated.
`
`Comments for 74-Day Letter
`
`You state in Module 3.2.S.1.3 that dimethyl fumarate is classified as BCS classification I.
`Provide data to support this classification or identify the location of the data in the NDA
`submission.
`
`We will review the data provided to support your proposal to exclude testing
`(b) (4)
`in the bulk drug substance. In the interim, we request that you provide the analytical method,
`and supporting validation data, for review.
`
` [Table 2, Module 3.2.P.1] to include the actual
`Revise the composition
`(b) (4)
`amounts of polysorbate 80 and sodium lauryl sulfate present
`.
`(b) (4)
`
`With regard to formulation development [Module 3.2.P.2.1] provide a tabular summary of all
`drug product batches used in Phase 1, 2, and 3 clinical studies (including clinical pharmacology
`and bioequivalence studies), and stability studies. Identify the specific studies in which each
`batch was used. If any of the clinical or stability batches differed from the proposed commercial
`product, the qualitative and quantitative formulation should be provided.
`
`With respect to the manufacturing process and manufacturing process development; provide data
`to support the proven acceptable ranges (PARs) given in Module 3.2.P.2.3 and the in-process
`controls given in Module 3.2.P.3.3.
`
`Revise the drug product dissolution test to include all equipment, instrument parameters, and
`solution preparations necessary for quantitation of the dissolution results by HPLC.
`
`Revise the container closure information in Module 3.2.P.7 to include the details of the proposed
`commercial HDPE bottle packaging configurations (i.e., capsule strength, capsule count, and
`bottle size).
`
`Reference ID: 3101584
`
`Page 10 of 17
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`

`NDA 204-063 Initial Quality Assessment
`
`Page 11
`
`With regard to drug product stability:
`
`Provide details regarding the HDPE bottle configurations (i.e., bottle size and tablet count)
`studied for the 120 mg primary validation batches (Batch Numbers 27664, 27665 and 27666)
`and the 240 mg primary validation batches (Batch Numbers 56060, 556061, and 56062).
`
`Provide headspace and surface area information to justify the HDPE bottle bracketing
`approach used in the stability protocols for Batches 47823, 47824, 47825, 54164, 54165, and
`54166.
`
`You have provided graphical presentations of regression analyses
`(b) (4)
` in 120 mg capsules in Module 3.2.P.8.1. Provide details of the of the
`statistical analyses performed, including batches analyzed, whether data from batches were
`pooled, and statistical output.
`Review, Comments and Recommendation:
`The NDA is fileable from a CMC perspective; however additional information should be
`requested in the 74-Day letter.
`
`The drug substance is a well-characterized small molecule and the drug product is a simple
`immediate release tablet. There are no QbD aspects to the NDA submission. It is recommended
`that the review team include a single CMC reviewer and a Biopharmaceutics reviewer. The drug
`substance is a new molecular entity; therefore, a Division-level regulatory briefing would be
`appropriate. Methods Validation studies should be requested if the application is filed.
`
`{See appended electronic signature page}
`Martha R. Heimann, Ph.D.
`CMC Lead, DNDQA-1, ONDQA
`
`{See appended electronic signature page}
`Ramesh Sood, Ph.D.
`Branch Chief, DNDQA-1, ONDQA
`
`Reference ID: 3101584
`
`Page 11 of 17
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`

`

`NDA 204-063 Initial Quality Assessment
`
`1
`
`ATTACHMENT 1
`
`Manufacturing Establishments for Dimethyl Ftunarate Capsules
`
`Manufactming inf01mation is reproduced from the attachment to Form 35611.
`
`DRUG SUBSTANCE
`
`~----------------------------------------------------------------------~~~
`
`DRUC PRODUCT
`~-----------------------------------------------------------------------.~~
`
`All facilities have been submitted in EES.
`
`Reference ID: 3101584
`
`Page 12 of 17
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`

`

`CHEMICAL MANUFACTURING CONTROLS
`FILING CHECKLIST FOR A NEW NDAIBLA
`
`NDA Number:
`204-063
`
`Applicant:
`Biogen Idee.
`
`Supplement Number and Type:
`N/A
`
`Letter Date:
`24-Feb-2012
`
`Established/Proper N arne:
`Dimethyl Fumarate Delayed Release
`Capsules
`Stamp Datt>:
`27-Feb-2012
`
`The following parameters are necessary in order to initiate a filii review, i.e., complete enough to review but may
`have deficiencies. On !!!!lli!! overview of the NDA application for filing:
`
`A. GEJ'oo'ERAL
`Yes
`No
`
`Commt>nt
`
`X
`
`X
`
`X
`
`X
`
`B. FACILITIES*
`Yes
`No
`
`Comment
`
`X
`
`N IA
`
`X
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Pammetet·
`Is the CMC section organized
`adequately?
`Is the CMC section indexed and
`paginated (including all PDF files)
`adequately?
`Are all the pages in the CMC section
`legible?
`Has all information requested during the
`lND phase, and at the pre-NDA meetings
`been included?
`
`Pat·ametet·
`Is a single. comprehensive list of all
`involved facilities available in one
`location in the application?
`For a naturally-derived API only, are the
`facilities responsible for critical
`intetmediate or crude API manufacttu·ing,
`or performing upstream steps, specified
`in the application? If not, has a
`justification been provided for this
`omission? This question is not
`apJllicable for SJ'Dtbeslzed API.
`Are dmg substance manufacturing sites
`identified on FDA Foml356h or
`associa1ed continuation sheet? For each
`site, does the application list:
`• Name of facility,
`• Full address of facility including
`street, city, state, co\mtry
`• FEI number for facility (if previously
`registered with FDA)
`• Full name and title, telephone, fax
`number and email for on-site contact
`person.
`• Is the manufacntring responsibility
`and thnction identified for each
`facility?, and
`• DMF number (if applicable.)
`
`Reference ID: 3101584
`
`Page 13 of17
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`

`

`NDA 204-063 Filing Checklist, Page 2
`
`X
`
`X
`
`Are drug product manufacturing sites
`identified on FDA F01m 356h or
`associated continuation sheet? For each
`site, does the application list:
`• Name of facility,
`• Full address of facility including
`street, city, state, country
`• FEI number for facility (if previously
`registered with FDA)
`• Full name and title, telephone, fax
`mm1ber and email for on-site contact
`person.
`• Is the manufa.cturing responsibility
`and ftmction identified for each
`fa.cility?, and
`• DMF number (if applicable)
`Are additional manufacntring, packaging
`and c.ontroVtesting laboratory sites
`identified on FDA Fonn356h or
`associated continuation sheet. For each
`site, does the application list:
`• Name of facility,
`• Full address of facility including
`street, city, state, conntry
`• FEI number for facility (if previously
`registered with FDA)
`• Full name and title, telephone, fax
`nnn1ber and email for on-site contact
`person.
`• Is the manufacturing responsibility
`and ftmction identified for each
`facility?, and
`• DMF number (if applicable)
`Is a statement provided that all facilities
`are ready for GMP inspection at the time
`of submission?
`...
`If any mfonuauon regarding the facdtttes ts otmtted, tius should be addressed ASAP wtth the applicant and can be a
`potential filing issue or a potential review issue.
`
`X
`
`P at·ametet·
`Has an environmental assessment cepott
`or categorical exclusion been provided?
`
`c. ENVIRONMENTAL ASSESSMENT
`Yes
`No
`
`Comment
`
`X
`
`Categorical exclusion claimed.
`
`8 .
`
`9.
`
`10.
`
`+
`
`11.
`
`Reference ID: 3101584
`
`Page 14 of17
`
`

`

`NDA 204-063 Filing Checklist, Page 3
`
`12.
`
`13.
`
`15.
`
`16.
`
`D. DRUG SUBSTANCE/ACTIVE PHARMACEUTICAL INGREDIENT (DS/API)
`Pru·nmet<>I'
`Y<>s
`No
`Comm<>nt
`Does the section contain a description of
`the DS manufacturing process?
`Does the s~tion contain identification
`and controls of critical steps and
`intermediates of the DS?
`14. Does the s~tion contain information
`re!!arding the characterization of the DS?
`Does the s~tion contain controls for the
`DS?
`Has stability data and analysis been
`I provided for the dt1.tg substance?
`Does the application contain Quality by
`17. Design (QbD) infonnation regarding the
`DS?
`Does the application contain Process
`18. Analytical Teclmology (P A 1)
`infonnation ree.arding the DS?
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`19.
`
`20.
`
`2L
`
`22.
`
`24.
`
`25.
`
`26.
`
`P1u am etu
`Is there a description of manufacttuing
`process and methods for DP production
`through finishing, including fonn ulation ,
`filling, labeling and packa<riua?
`Does the section contain identification
`and controls of critical steps and
`intennediates of the DP, including
`anal)1ical procedm·es and method
`validation reports for assay and related
`substances if applicable?
`Is there a batch production record and a
`I proposed master batch record?
`Has an investigational formulations
`section been provided? Is there adequate
`linkage between the investigational
`product and the proposed marketed
`I product?
`23. Have any biowaivers been requested?
`Does the section contain description of
`to-be-marketed conta.iner/closme system
`and presentations)?
`Does the section contain controls of the
`final drug product?
`Has stability data and analysis been
`provided to support the requested
`expiration date?
`Does the application contain Quality by
`27. Design (QbD) infonnation regarding the
`DP?
`Does the application contain Process
`28. Analytical Technology (PAT)
`inf01mation reRarding the DP?
`
`E. DRUG PRODUCT (DP)
`Yes
`No
`
`Commt>nt
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`A detailed listing of clinical batches and clinical studies will
`be requested however, the proposed commercial products are
`linked to Phase 3 formulation as follows:
`120 mg difference is capsule CD1roll color - dissolution data
`240 mg bv bioeuuivalence collll>arison to 2 x 120 mg
`
`(tiiT•l HDPE bottles proposed and described; however,
`details about commercial HD PE presentations (capsule count
`and bottle size) need to be clarified.
`
`I
`Paramt>ter
`I Is there a methods validation pack8.Jl;e?
`
`F. METHODS VALIDATION (MV)
`I Yes I No I
`Commt>nt
`I Not critical for review of electronic submission.
`I
`I X
`
`29.
`
`Reference ID: 3101584
`
`Page 15 of 17
`
`

`

`NDA 204-063 Filing Checklist, Page 4
`
`Parameter
`If appropriate, is a separate
`microbiological sec tion included
`assurin<> sterility of the drug product?
`
`G. MICROBIO L OGY
`Y<1s
`No
`
`Comment
`
`N /A
`
`H. MASTER FILES (DMFIMAF)
`Yes
`No
`
`Paramt.>ter
`Is information for critical DMF
`references (i.e., for dmg substance and
`impo11aut packaging components for
`non-solid-oral drug products) complete?
`
`X
`
`I DMF # I TYPE I HOLDER
`
`l iTEM REFERENCED
`
`COMMENTS
`
`Comment
`
`LOA DATE
`-lDJT4 04-May-2011
`04-May-2011
`03-Mav-2011
`10-Jan-2011
`04-May-201 1
`04-May-2011
`03-Mav-2011
`27-Jun-2011
`17-Jan-2012
`17-Jan-2012
`05-May-2011
`27-Jun-20 11
`
`04-Mav-2011
`
`30.
`
`31.
`
`32.
`
`33.
`
`34.
`
`35.
`
`36.
`
`Parameter
`Has the draft package inseti been
`I provided?
`Have the inunediate container a11d
`catton labels been provided?
`
`I. LABELING
`Yes
`No
`
`Commt>nt
`
`X
`
`X
`
`Parameter
`I s the pt·oduct q u ality st>c.tion of the
`llppliclltion filpabl<! ?
`If the NDA is not fileable from the
`product quality perspective, state the
`reasons a11d provide filing comments to
`be sent to the Applicant.
`Are there any p otPntial t"P"iPw issues to
`be forwarded to d1e Applicant for the
`74-day letter?
`
`J. FILING CONCLUSION
`Yes
`No
`
`Comment
`
`X
`
`N/A
`
`Describe filing issues here or on additional sheets
`
`Describe potential review issues het·e or on additional sheets
`
`{See appended ele.ctronic sir:nature pafte}
`Martha R. Heimallll, Ph.D.
`CMC Lead, DNDQA-1, ONDQA
`
`{See appended electronic signatttre page)
`Ramesh Sood, Ph.D.
`Branch Chief, DNDQA-1 , ONDQA
`
`Reference ID: 3101584
`
`Page 16 of17
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`MARTHA R HEIMANN
`03/14/2012
`
`RAMESH K SOOD
`03/14/2012
`
`Reference ID: 3101584
`
`Page 17 of 17
`
`