`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`204063Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DATE:
`
`FROM:
`
`SUBJECT:
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`20 MAR 2013
`
`David J. Claffey, PhD
`
`Approval recommendation for NDA 204063
`
`
`
`
`
`
`On 20 MAR 2013 CDER Office of Compliance issued and overall acceptable recommendation
`for the manufacturing sites associated with this application. An approval recommendation for
`this application can now be made from a CMC perspective.
`
`
`
`Reference ID: 3279868
`
`

`

`ATTACHNIENT
`
`0C Recommendation
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Application:
`Om. Code:
`Priority:
`M Date
`PDUFA DI“
`Adieu Goal
`DIUMuGod
`
`FDA Cont-us:
`
`NDA 204m
`120
`1
`27-FE—2012
`27-MAR~2013
`
`IMAM-2013
`
`T. BOUIE
`DI CLAFFEY
`M7 HEIMANN
`
`Project Manager
`Review Chan's!
`Team Leader
`
`890!”
`
`BIOGEN IDEC INC
`14 CAABRDGE CENTER
`CAMBRIDGE, MA 02142
`findhylWe
`
`Brand m:
`Emb. Name:
`dinethyl funaralo
`We NI'IIO:
`Product Hunter, Dosage Fonn; Median; W
`001. CAPSULE. DELAYED ACTION. DINETHYL FUMARATE; 12(MG
`M2; CAPSLIE, DEAYED ACTION: DIIETHYL FUMARATE', 24m
`3017961649
`3017961343
`3017961678
`
`OverallWon:
`
`ACCEPTABLE
`PENDING
`
`on 20MAR-2013
`m 08-MAR-2012
`
`by Dr SMITH
`by EES_PROD
`
`(HFD«323)
`
`3017965321
`
`PENDING
`on DOW-2012 by EES_PROD
`
`Edabflohmlnt
`
`
`
`NONE
`
`0C RECOMNENDATION
`20-MAR—2012
`
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`DMF No:
`Responsibilifies:
`
`Profile
`
`mm;
`“lotion. Duh
`
`MIMI
`Reason:
`
`Reference ID: 3279868
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`
`
`AADA:
`
`OAI sum:
`
`NOME
`
`06 RECOIMENDATION
`1 1m—2012
`ACCEPTABLE
`BASED ON PROFILE
`
`
`
`0C RECWENDATION
`1 1-MAR—2012
`ACCEPTABLE
`BASED ON PROFILE
`
`
`
`AADA:
`
`OAI m:
`
`NOIE
`
`0C RECOMMENDATION
`"MAR-2012
`ACCEPTABLE
`BASED ON PROFILE
`
`mum
`
`DIE No:
`Rnpomlbllmoo:
`
`PM“:
`
`mm;
`mm. M:
`Dochlnn:
`m:
`
`mum
`
`DIE No:
`
`Mmflblllfla:
`Profile:
`
`mm;
`"WI. Du:
`Docblon:
`lip-son:
`
`mm
`
`DIE No:
`Rnponslblllths:
`Promo:
`
`Latm;
`III-dune I)“:
`Decisim:
`Ramon:
`
`Reference ID: 3279868
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUA'I10N REQUEST
`SUMMARY REPORT
`
`
`
`MODE
`
`0C REWDATION
`11-MAR-2012
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`
`
`0C RECOMMENDATION
`18-MAR-2013
`
`ACCE’TABLE
`
`DISTRICT RECOMMENDATION
`
`
`
`0c RECCMENDATION
`
`”MARX,”
`ACCE’TABLE
`
`DISTRICT RECOMMENDATION
`
`MODE
`
`NOI£
`
`Eat-fliahment:
`
`DMF No:
`
`mum:
`Prollo:
`
`Lat mm“
`“lemon: Date:
`
`m;
`
`Reason:
`
`wishment:
`
`DMF No:
`
`Responlibiilils:
`
`Proilo:
`
`Lest mm;
`“lemon. Dah:
`
`Decblou:
`
`Rel-on:
`
`Edfllishment:
`
`DMF No:
`
`Ruponubllflu:
`
`Profile:
`
`m ”We;
`
`Electone Date:
`Decision:
`
`Reason:
`
`Reference ID: 3279868
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DAVID J CLAFFEY
`03/20/2013
`
`RAMESH K SOOD
`03/21/2013
`
`Reference ID: 3279868
`
`

`

`ONDQA Division Director’s Memo
`NDA 204-063,
`mm (dimethylfilmarate delayed release capsules)
`120 and 240 mg
`Date: 13-FEB-2012
`
`Introduction
`am) is a delayed-release capsule formulation to be marketed in two strengths — 120 and
`240 mg. Both strengths were reviewed for adequacy as part of the current review. All excipients
`are commonly used in solid oral dosage forms. The two tablet strengths are qualitatively similar
`with ‘5’“) exceptions: the 240 mg strength does not include mm (as is present in the lower dosage
`strength), and
`M4) were used in the respective
`dosage strengths.
`
`mm is 120 mg, twice daily and taken for the first
`The recommended starting dose of
`seven days. followed by a daily dose of 240 mg, twice daily and thereafter.
`«am can be
`taken with or without food.
`
`All CMC-related deficiencies have been resolved for this application, and all related reviews are
`complete. There are no outstanding review deficiencies that would preclude a recommendation
`of approval from a CMC standpoint. An overall acceptable recommendation from the Office of
`Compliance has not yet been issued.
`
`All CMC review issues have been resolved, and ONDQA recommends approval ofthis NDA
`pending the receipt ofan overall acceptable recommendation from the Oflice of Compliance.
`
`Administrative
`
`The original submission of this 505(b)(1) NDA was received on 27-FEB-2012 from Biogen Idec,
`Inc. Six (6) CMC amendments were also reviewed during the review cycle. The comprehensive
`CMC assessment is captured in the following reviews, respectively: Chemistry Review #1 (l9-
`NOV—2012, Dr. D. Claffey), Biopharmaceutics Review (l9—NOV—2012, Dr. E. Chikhale), and the
`Biopharmaceutics Review Addendum (12-FEB-2013).
`
`The NDA is supported by thirteen (13) drug master files (DMFs). All DMFs were assessed for
`adequacy in the chemistry review.
`
`Reference ID: 3261296
`
`

`

`Drug Substance (dimethyl fumarate)
`Chemical Name: Dimethyl (E)-butenedioate
`
`0
`
`0
`
`MW = 144.1 ymol
`€511.04
`
`Dimethyl fumarateIS an achiral trans-butene diester andIS a new molecular entity. It has limited
`eous solubili
`3-4
`ml but
`ssesses hi
`er solubility1n methanol (ca 30 mg/ml). -
`Dimethyl funnraters non-hygroscopic
`
`Dimethyl fumarate is relativel stable; no extraordinary storage precautions are required The
`proposed re—test period
`when stored in the recommended container closure system
`under the proposed storage conditions
`is granted
`
`Drug Product (dimethyl fumarate delayed release capsules)
`
`The
`,120 m and 240
`,in Size-0 hard-gelatin
`The 120 mg strength has a
`
`e 240 mg strength has a green body
`“BG-12 120 mg”.
`
`“BG-12 240 mg”. The capsules will be packaged in HDPE bottles.
`
`
`
`The drug product formulation was designed to prevent release of the drug substance in the
`
`stomachwhile allo '
`
`a rapidrelease in the intestine. The formulation consistsF
`
`e same
`a size-0 hard gelatin capsule. Although both strengths share
`er quantitatively and in some more minor respects, qualitatively. Additional
`ey
`e Size,
`c
`and specific formulation details can be located in the l9—NOV-2012 Chemistry Review by Dr. D.
`Clafl‘ey.
`
`
`
`expiry for this product when stored in the commercial
`The Applicant proposed a
`on e stability data provided and in accordance with ICH QlE, the
`packaging at 530°C. B
`Agency grants an actual expiry of 18 months for the 120 mg strength, and 9 months for the 240
`mg strength Due to the discrepancy between the proposed and granted expiration dating periods,
`
`Reference ID: 3261296
`
`

`

`I concur with the primary reviewer that appropriate confirmatory language regarding
`expiration dating is needed in the action letter (see page 7 of the Chemistry Review).
`
` also concur with the Chemistry review team’s recommendation of approval pending an
`overall “Acceptable” recommendation from the Office of Compliance.
`
`
`
`
`
`
`
`
`
` I
`
`Reference ID: 3261296
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SARAH P MIKSINSKI
`02/13/2013
`
`Reference ID: 3261296
`
`

`

`Initial Quality Assessment
`Branch I
`
`Division of New Drug Quality Assessment I
`
`0ND Division: Division of Neurology Products
`NDA: 204-063
`
`Applicant: Biogen Idec Inc.
`Stamp Date: 27-Feb-2012
`PDUFA Date:
`
`is proposed
`Trademark:
`Established Name: Dimethyl fumarate [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
`[Z
`ONDQA Fileability:
`[:1
`Comments for 74-Day Letter E E]
`
`Summary and Critical Issues:
`
`Summary
`
`Dimethyl fumarate (BG00012) has been developed by Biogen-Idec as a novel treatment for
`relapsing forms of multiple sclerosis (MS). The pharmacological properties of BG00012 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 primary cellular defense system
`for responding to a variety of potentially toxic stimuli.
`
`The current NDA provides for a delayed release dimethyl fumarate capsule formulation
`. Two strengths are proposed, 120 mg and 240 mg. The
`product is intended for use in the treatment of patients with relapsing forms of multiple sclerosis
`(MS)
`(we)
`The recommended starting dose is 120 mg taken twice daily for seven days, followed
`by increase to the target dose of 240 mg taken twice daily.
`
`Prior to submission of the NDA the applicant sought Agency feedback during a Type C CMC-
`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—Jun-2011 to IND 73,061, is
`available in the EDR. Key issues addressed during the meeting are summarized below.
`
`0 Based on information provided in the briefing package, the Agency agreed to designation
`of
`M” as the regulatory starting material.
`
`mm durin manufacture of the
`0 There is a potential for formation of
`drug substance. The applicant proposed not including a test for w in the drug product
`specification based on kinetic modeling and spiking experiments. The Agency initially
`
`Reference ID: 3101584
`
`

`

`NDA 204-063 Initial Quality Assessment
`
`Page 2
`
`recommended that the applicant continue testing- in at least the first ten
`commercial batches before requesting deletion of the test from the specification. During
`the meeting, however, the Agency agreed that the firm could present the rationale for
`deleting the specification, and additional supporting data not included in the briefing
`package, in the NDA filing for review.
`
`0 The applicant proposed that no drug substance or drug product manufacturing process
`parameters be designated as critical. The firm was advised to submit the development
`reports that included the rationale why there are no critical process parameters, including
`parameters that were not studied.
`
`0 The applicant requested concurrence with the proposed dissolution method and was
`advised to submit a fill] 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 concurred with the proposed method.
`
`0 The Agency agreed that the proposed characterization testing to qualify the higher
`strength (240 mg capsule) would be adequate provided the applicant conduct the
`proposed bioequivalence study. With respect to the proposed stability package for the
`higher strength, the firm 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 months update during the review cycle.
`
`Drug Substance
`
`The active ingredient, dimethyl filmarate [systematic name: (E)-2-butenedioic acid dimethyl
`ester], is a neutral small molecule with molecular formula C5H804 and molecular weight 144.13.
`The drug substance is slightly soluble in water (2.84 mg/mL) and aqueous buffers.
`em
`The applicant indicates that dimethgl
`Q
`
`fumarate should be classified as BCS Class 1.
`
`‘The chemical structure ofdimethyl fumarate is:
`
`The dru substance is not hygroscopic; however, it is reported to be
`
`\
`
`All information regarding manufacturing and
`characterization of the drug substance is provided in the NDA itself; no DIVIFs are referenced. It
`is noted that although two separate 3.2.S modules are provided for the two suppliers, the
`
`Reference ID: 3101584
`
`

`

`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]
`
`.
`
`•
`
`• Different control strategies will be used during manufacture at the two sites.
`
`• 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
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Identification A
`
`.
`
`Identification B
`
`Retention time of the sample peak
`corresponds to the retention time
`of the reference standard
`
`IR spectrum of the sample
`corresponds to the IR spectrum of
`
`NDA 204-063 Initial Quality Assessment
`
`Page 4
`
`Table 1:
`
`Release Specification for Drug Substance
`
`w—I
`
`-
`
`the reference standard
`
`ical for a small
`The specification for dimethyl fumarate includes test parameters that are
`
`HPLC
`molecule. Assay and Related Substances are determined by a
`method using an acetonitrile/O. 1% aqueous phos horic acid mobile base and UV detection at
`
`210 nm. There are two specified impurities,
`
`. As noted above, the applicant proposes to exclude
`from the specification. The justification provr e is based
`on the chemistry of the synthesis, kinetic modeling experiments, spiking studies, and batch
`analyses.
`
`The drug substance primary stability package includes long-term (25°C/60% R. H.) and
`intermediate data (30°C/65% R. H.) through 60 months and accelerated data 40°C/75% R. H.)
`through six months for three commercial scale batches manufactured
`. Six
`months of data are provided for three commercial scale batches manufactured
`; however,
`for
`batches only samples stored the intermediate and accelerated conditions were tested.
`Ad tlonal supportive data are also provided. A- retest date is proposed.
`
`
`
`Reference ID: 3101584
`
`

`

`NDA 204-063 Initial Quality Assessment
`
`Page 5
`
`Drug Product
`
`The ro osed dosa e form is a dela ed release capsule consisting of size 0 hard gelatin capsules
`
`Two capsule strengths are proposed. The 120 mg
`
`
`; 240 mg capsules have a green body”. Both
`capsules have a white body with gree
`strengths will be irinted with a product 1 entifier (not specified in the application .
`Table 2: Theoretical Composition of Dimethyl Fumarate_
`
`compositions
`
`presented in Module 3.2.P.l are summarized in Table 2 below.
`
`e
`
`Component
`
`Ingredient
`
`éfimeunfinersmesq'almgl W. ..
`120 mg
`240 mg
`
`Dimethyl fumarate
`Croscarmellose sodium
`
`Active ingredient
`
`Microcrystalline cellulose-
`
`Silicified microcrystalline
`
`
`Magnesium stearate 1
`
`Talc
`
`Colloidal silicon dioxide
`
`Subtotal
`
`Methacrylic acid copolymer, Type
`
`
`
`Methacrylic acid copolymer
`dispersion (includes Sodium
`
`lauryl sulfate. Polysorbate 80) 2
`Triethyl citrate
`
`Reference ID: 3101584
`
`

`

`NDA 204-063 Initial Quality Assesnent
`
`Page 6
`
`are proportional. The finished 120
`; 240 mg capsules contain
`
`
`ca sules contain
`.
`
`The formulation and manufacturing process development history for Dimethyl Fumarate
`Capsules are presented as narratives in the Pharmaceutical Develo ment Section; however,
`limited data are provided. Note that the manufacturing process
`
`
`
`. It is recommended that the 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 tn'als and primary stability batches were blue-
`white capsules rather than the proposed green-white. Additional information will be requested.
`
`Dimethyl Fumarate Capsules will be manufactured
`
`
`
`The manufacturing process development report
`presents a traditional approach to process development. Limited data are provided to support the
`selected process parameters and operating ranges.
`
`Reference ID: 3101584
`
`

`

`NDA 204-063 Initial Quality Assessment
`
`Page 7
`
`The proposed specifications for Dimeth lFumarate Ca sules are summarized in Table 3. The
`drug substance process impurities,
`are both specified
`as potential degradation products, w1
`g su stance.
`
`er
`
`ts
`
`an or
`
`e
`
`Table 3: Specifications for Dimethyl Fumarate Capsules
`
`! Test
`
`!—A“°Pta“?g Crltena
`120 mg
`
`Description
`
`Capsule
`
`Visual Inspection
`
`Visual Inspection
`
`Retention time of the sample peak corresponds to the retention time
`of the reference standard
`
`UV spectrum of the sample peak corresponds to the UV spectrum of
`the reference standard
`
`
`
`GC
`
`CUS‘P #9055,
`Ph. Eur. 2.9.40
`
`usp <711>,
`Ph. Eur. 2.9.3
`
`Analytical procedures are straightforward. Assay, and Content Uniformity are determined using
`the reverse phase HPLC [C18 column, pH 3.15 phosphate buffer—methanol 50:50 mobile phase
`and UV-PDA detection at 223 nm]. A related HPLC method using a 60:40 buffer—methanol
`mobile phase is used for determination of impurities. Dissolution is determined 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 summary data is provided in Module
`3.2.P.5.5; the methods validation reports are provided in Module 3.2.R.
`
`Dimethyl Fumarate Capsules will be ackaged in HDPE bottles with aluminum foil induction
`seal, white polypropylen
`closure and cotton filler,
`Module 3.2.P.7 contains
`ormation regarding four sizes of HDPE ott es
`
`F however the details ofthe proposed commercial presentations (capsule strength,
`
`ott e count and bottle size) are not provided.
`
`The NDA stability package is summarized in Tables 4 and 5. The applicant proposes-
`expiry for both strengths in- HDPE bottles.
`
`Reference ID: 3101584
`
`

`

`NDA 204-063 Initial Quality Assessment
`
`Page 8
`
`Table 4: Summary of Dimethyl Fumarate Capsule Batches Packaged in HDPE Bottles
`
`
`0°C/75% R. H.
`
`Batch Type
`
`jeepsule
`;Strength
`
`:Capsule
`;Color
`
`Validation
`
`§EBIue-white
`
`Green-white
`
`Registration
`
`;
`
`.
`
`47824
`
`47825
`
`54164
`54165
`54166
`
`ECapsule Count! ZStorage
`Bottle Size
`
`EData Available
`Months)
`
`5°C/60% R. H.
`.
`.
`§N°tdesmbedm 0°C/65% R. H.
`0°C/75% R. H.
`
`Not described in
`NDA
`
`0°C/65% R. H.
`0°C/75% R. H.
`
`:48
`:48
`gr;
`
`0
`0
`
`14/60 cc
`42l120 cc
`180/325 cc
`
`14/60 cc
`120/215 cc
`
`42/120 cc
`
`120/215 cc
`14/60 cc
`60/120 cc
`90/215 cc
`
`0°C/65% R. H.
`0°C/75% R. H.
`
`0°C/65% R. H.
`
`With respect to the stability data and proposed expiry the following key points are noted.
`
`0 The rinci a1 de adation athwa for dimeth lfumarate is
`
`in
`
`
`
`HDPE
`tt es and
`
`is likely to be the stability limiting factor. The applicant has provided the results of
`
`Reference ID: 3101584
`
`

`

`NDA 204-063 Initial Quality Assessment
`
`Page 9
`
` 120 mg capsules as graphical presentations; it is
`regression analyses for
`recommended that detailed information be requested.
`
`• 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
`all storage conditions. The applicant proposes the same expiry
` for 240 mg
`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
`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
`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
`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
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`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
`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
`amounts of polysorbate 80 and sodium lauryl sulfate present
`.
`
`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
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`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
` 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
`
`(b) (4)
`
`

`

`NDA 204-063 Initial Quality Assessment
`
`1
`
`ATTACHMENT 1
`
`Manufacturing Establishments for Dimethyl Fumarate Capsules
`
`Manufactun'ng information is reproduced from the attachment to Form 356h.
`
`DRUG SUBSTANCE
`
`DRUG PRODUCT
`
`
`
`
`All facilities have been submitted in EES.
`
`Reference ID: 3101584
`
`

`

`CHENIICAL MANUFACTURING CONTROLS
`
`FILING CHECKLIST FOR A NEW NDA/BLA
`
`NDA Number:
`204-063
`
`Applicant:
`Biogen Idec
`
`Supplement Number and Type:
`N/A
`
`Letter Date:
`24-Feb-2012
`
`Established/Proper Name:
`Dimethyl Fumarate Delayed Release
`Capsules
`Stamp Date:
`27-Feb-2012
`
`The following parameters are necessary in order to initiate a full review. i.e.. complete enough to review but may
`
`have deficiencies. On initial overview of the NDA application for filing:
`
`A. GENERAL
`
`__
`Is the CMC section organized
`X
`ad- a uatel ?
`Is the CMC section indexed and
`
`2.
`
`3.
`
`paginated (including all PDF files)
`ad a uatel ?
`
`Are all the pages in the CMC section
`.
`le 1ble?
`
`X
`
`X
`
`Has all information requested during the
`[ND phase. and at the pre-NDA meetings
`been included?
`
`X
`
`FACILITIES*
`
`
`
`-—-m—
`Is a single. comprehensive list of all
`involved facilities available in one
`location in the a t o lication?
`
`X
`
`5.
`
`For a naturally-derived API only. are the
`facilities responsible for critical
`intermediate or crude API manufacturing.
`or performing upstream steps. specified
`in the application? Ifnot. has a
`justification been provided for this
`omission? This question is not
`a. ulicable for synthesized API.
`
`Are drug substance manufacturing sites
`identified on FDA Form 356h or
`associated continuation sheet? For each
`
`site. does the application list:
`0 Name of facility.
`0 Full address of facility including
`street. city. state. country
`0 FEI number for facility (if previously
`registered with FDA)
`0 Full name and title. telephone. fax
`number and email for on-site contact
`person.
`
`0 Is the manufacturing responsibility
`and function identified for each
`
`facility?. and
`0 DMF number if a y. licable
`
`Reference ID: 3101584
`
`

`

`NDA 204-063 Filing Checklist. Page 2
`
`Are drug product manufacturing sites
`identified on FDA Form 356h or
`associated continuation sheet? For each
`
`site. does the application list:
`0 Name of facility.
`0 Full address of facility including
`street. city. state. country
`0 FE] number for facility (ifpreviously
`registered with FDA)
`0 Full name and title. telephone. fax
`number and email for on-site contact
`
`person.
`
`0 Is the manufacturing responsibility
`and function identified for each
`
`facility?. and
`O DMF number if a go licable
`Are additional manufacturing. packaging
`and control/testing laboratory sites
`identified on FDA Form 356h or
`associated continuation sheet. For each
`
`site. does the application list:
`0 Name of facility.
`0 Full address of facility including
`street. city. state. country
`0 FBI number for facility (if previously
`registered with FDA)
`0 Full name and title. telephone. fax
`number and email for on—site contact
`person.
`
`0 Is the manufacturing responsibility
`and flmction identified for each
`
`facility?. and
`o DMF number ifa '
`
`X
`
`X
`
`
`
`Is a statement provided that all facilities
`are ready for GMP inspection at the time
`of submission?
`
`X
`
`*
`
`If any information regarding the facilities is omitted. this should be addressed ASAP with the applicant and can be a
`potential filing issue or a potential review issue.
`
`or cate ~ oncal exclusron been rowded?
`
`__
`l 1. Has an environmental assessment report
`X
`Categorical exclusion claimed.
`
`ENVIRONNIENTAL ASSESSMENT
`
`Reference ID: 3101584
`
`

`

`NDA 204-063 Filing Checklist. Page 3
`
`DRUG SUBSTANCE/ACTIVE PHARMACEUTICAL INGREDIENT I S/AP
`
`-—-m—
`
`.the DS manufacturin rocess?
`
`Does the section contain identification
`
`l3.
`
`and controls of critical steps and
`intemlediates of the DS?
`
`X
`
`_I—re - ardin- the characterization of the DS?
`_I-—l 5.
`_I—. rovided for the dru substance?
`
`DS?
`
`X
`
`
`
`17.
`
`Does the application contain Quality by
`Design (QbD) information regarding the
`DS?
`
`Does the application contain Process
`Analytical Technology (PAT)
`information re - ardin- the DS?
`
`X
`
`X
`
`_E-_
`
`DRUG PRODUCT I P
`
`15 there a description of manufacturing
`process and methods for DP production
`through finishing. including fonnulation.
`fillin . labelin- and acka-'
`-?
`Does the section contain identification
`
`and controls of critical steps and
`intermediates of the DP. including
`analytical procedures and method
`validation reports for assay and related
`substances if an n licable?
`
`X
`
`X
`
`_II—‘
`
`to o osed master batch record?
`
`Has an investigational formulations
`section been provided? Is there adequate
`linkage between the investigational
`product and the proposed marketed
`. roduct?
`
`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:
`lb) (4)
`120 mg difference is capsule
`color — dissolution data
`240 nl b bi - uivalence con .arison to 2 x120 m
`
`_ Havean biowaiversbeenreuested? ii
`M“) HDPEbottlesproposedanddescribed;however.
`I Doesthesectioncontaindescriptionof
`to-be-marketedcontainer/closuresystem..detailsaboutcommercialHDPEpresentations(capsulecount
`
`and bottle size) need to be clarified.
`
`and presentations)?
`Does the section contain controls of the
`final dru -
`: oduct?
`
`Has stability data and analysis been
`provided to support the requested
`ex u iration date?
`
`Does the application contain Quality by
`Design (QbD) information regarding the
`
`Does the application contain Process
`Analytical Technology (PAT)
`information re ardin the DP?
`
`NIETHODS VALIDATION W_-_
`
`IsIthere a methods validation package? -- Not critical for review of electronic submission.
`
`Reference ID: 3101584
`
`

`

`NDA 204-063 Filing Checklist. Page 4
`
`
`
`G. MICROBIOLOGY
`
`__
`If appropriate. is a separate
`microbiological section included
`asstnin- sterili of the dru-
`roduct?
`
`
`30.
`
`H. MASTER FILES
`__
`Is information for critical DMF
`
`references (i.e.. for drug substance and
`important packaging components for
`non-solid—oral drug products) complete?
`
`DMF# TYPE
`
`HOLDER
`
`ITEM REFERENCED
`
`_OMMENTS
`
`LOA DATE
`“‘4’04-Ma -2o11
`04-Ma -2o11
`03-Ma -2o11
`10-Jan-2011
`04-Ma -2011
`04-Ma -2o11
`03-Ma -2o11
`27-Jun-2011
`17-Jan-2012
`17-Jan-2012
`05-Ma -2o11
`27-Jun-2011
`
` 04-Ma -201 1
`
`
`I. LABELING
`
`__
`Has the draft package insert been
`. rmided?
`Ha\-e the immediate container and
`carton labels been u'rmided?
`
`
`
`74-da letter?
`
`__
`34
`Is the product quality section of the
`X
`a Iication fileable?
`If the NDA is not fileable from the
`
`'
`
`FILING CONCLUSION
`
`N/A
`
`Describe filing issues here or on additional sheets
`
`Describe potential review issues here or on additional sheets
`
`product quality perspective. state the
`reasons and provrde filing comments to
`be sent to the Applicant.
`Are there any potential review issues to
`be forwarded to the Applicant for the
`
`Seen ended electronic si nat