`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`204654Orig1s000
`CHEMISTRY REVIEW(S)
`
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`

`

`Initial Quality Assessment
`Branch IV
`
`Division of New Drug Quality Assessment 11
`
`0ND Division: Division of Reproductive and Urologic Products
`NDA:
`204654
`
`Applicant: Warner Chilcott
`Stamp Date:
`27-Sep-2012
`PDUFA Date:
`26—Jul—2013
`
`Trademark: None provided
`Established Name: Norethindrone acetate/Ethinyl estradiol/Ferrous
`Fumarate
`
`Dosage Form: Tablet
`Route of Administration: Oral
`
`Indication: Prevention of pregnancy
`
`CMC Lead: Donna F. Christner, Ph.D.
`
`YES NO
`ONDQA Fileability: X
`I]
`Comments for 74-Day Letter D X
`
`Summary and Critical Issues:
`
`A. Summary
`
`The applicant has provided the following information on the drug product:
`
`(”(4)15 21 28-tablet oral contraceptive regimen consisting of the following (see l'lglll‘t.‘ 1):
`o Twenty-four
`”(amenable tablets [norethindrone acetate (NA). 1.0 mg and ethinyl
`estradiol (BE). 10 pg per tablet].
`a Two WC3016 mmtablets (BE. 10 pg per tablet).
`0 Two ferrous fumarate tablets. containing 75 mg of ferrous fumarate per tablet.
`The formulation for
`0') (0
`chewable tablets is based on a previously approved
`formulation. WC3016 "" ""tn L0 Loestrin (NDA 22-501). The main dilferenee between the two
`target product profiles was that
`0’) (4) tablets are intended to be chewable. The WC3016-
`(5) (”tablets and the ferrous fumarate tablets are previously approved products in NDA 22-501.
`
`one 1/10 chewable tablet formulation was based on the approved formulation for
`The
`L0 Loestrin Fe 1 mg NA/10 meg EE tablets (referred to in the NDA as WC3016 l/10 tablets
`gby its formulation WC3016 (no) tablets); a flavor and
`om) were added to
`one
`1/10 chewable tablets. The WC3016 EElO tablets are identical to L0 Loestrin Fe 10 mcg EE
`tablets. Lo Loestrin Fe received approval as an oral contraceptive on October 21, 2010 under
`NDA 022501 .
`
`The drug product is provided in a stande ow) blister pack The chewable combination tablets
`are contained in the first 24 wells of the blister pack. while the nonchewable ethinyl estradiol
`
`Reference ID: 32231 02
`
`

`

`tablets are contained in blister wells 25-26 and the inert, nonchewable ferrous fumarte tablets are
`in blister wells 27-28. The blister packaging is the same as used in the approved product under
`NDA 22501
`
`B. Critical issues for review
`
`All specifications are set based on the approved NDA 22501. Since these are immediate release
`tablets and the specifications are based on an approved NDA, consultation to ONDQA BioPharm
`may not be necessary. It is the primary reviewer’s decision on whether a BioPharm review is
`warranted.
`
`The combination tablet has only 6 months of stability data submitted in support of a 12 month
`expiration dating period. Although 6 months of data are less than what is currently
`recommended by ONDQA, based on the fact that the formulation is almost identical to an
`approved formulation except for the addition of sweetener and flavor,the amount of information
`is deemed adequate to allow review and to determine if 12 months of expiration dating period are
`appropriate.
`
`
`C. Comments for 74-Day Letter
`
`No comments to be conveyed at this time.
`
`D. Recommendation:
`
`This NDA is fileable from a CMC perspective. Gene Holbert, Ph.D. is assigned as the primary
`reviewer.
`
`REGULATORY BRIEFING RECOMMENDATION: Branch level.
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`_______________________
`Donna F. Christner, Ph.D.
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`Reference ID: 3223102
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`2
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`

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`NDA Number: 204654
`
`Type: 5
`
`Established/Proper Name:
`
`Norethindrone acetate and
`
`ethinyl estradiol chewable
`tablets, ethinyl estradiol
`tablets and ferrous fumarate
`tablets
`
`Applicant: Warner
`Chilcott
`
`Letter Date: 27—Sep—2012
`
`Stamp Date: 27—Sep—2012
`
`The following parameters are necessary in order to initiate a full review: i.e.. complete enough to
`
`review but may have deficiencies. 0n initial overview of the NDA application for filing:
`
`A. GENERAL
`
`__
`Is the CMC section organized
`ade c uatel
`;
`Is the CMC section indexed
`
`
`
`2.
`
`and paginated (including all
`PDF files) ade uatel
`:
`
`Are all the pages in the CMC
`section 1e 'ble?
`
`Has all information requested
`during the IND phase, and at
`the pre-NDA meetings been
`included?
`
`Is a single. comprehensive list
`of all involved facilities
`available in one location in the
`a D ulication?
`
`For a naturally-derived API
`only. are the facilities
`responsible for critical
`intermediate or crude API
`
`manufacturing. or perfomiing
`upstream steps. specified in the
`application? If not, has a
`justification been provided for
`this omission? This question
`is not applicable for
`svnthesized API.
`
`Reference ID: 32231 02
`
`

`

`7.
`
`8.
`
`Are drug substance
`manufacturing sites identified
`on FDA Form 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 number and email for on-
`site contact person.
`• Is the manufacturing
`responsibility and function
`identified for each facility?,
`and
`• DMF number (if applicable)
`Are drug product
`manufacturing sites are
`identified on FDA Form 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 number and email for on-
`site contact person.
`• Is the manufacturing
`responsibility and function
`identified for each facility?,
`and
`• DMF number (if applicable)
`
`X
`
`
`
`X
`
`
`
`
`
`
`
`
`
`Reference ID: 3223102
`
`4
`
`

`

`Are additional manufacturing.
`packaging and control/testing
`laboratory sites are identified
`on FDA Form 35611 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 function
`identified for each facility?.
`and
`
`
`
`Is a statement provided that all
`facilities are ready for GMP
`inspection at the time of
`submission?
`
`*
`
`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.
`
`C. ENVIRONMENTAL ASSESNIENT
`
`a n roved roduct Has an environmental
`
`__
`Categorical Exclusion as per 21 CFR 25.3 1(a)
`because it is a reformulation of an approved
`product and will substitute directly for the
`
`X
`
`assessment report or
`categorical exclusion been
`I rovided?
`
`Reference ID: 32231 02
`
`

`

`D. DRUG SUBSTANCE/ACTIVE PHARMACEUTICAL INGREDIENT IS/AP
`
`Norethidrone acetate: DMFs
`-
`-
`.
`Ethinyl estradrol. DMFs
`
`("Wand
`(hm)
`and
`
`0"“)
`(hm
`
`Norethidrone acetate: DMFs (m4) and M"
`Ethinyl estradiol: DMFs "M" and “M"
`
`(m4)
`
`0"“)
`
`Norethidroneacetate: DMFs M" and
`
`(m4)
`
`X
`
`X
`
`X
`
`X
`
`Not a filing issue
`
`.
`.
`Not a fihng Issue
`
`
`
`.
`~
`-
`and
`Ethinyl estradrol. DMFS
`(no)
`Norethidrone acetate: DMFs (m4) and
`Ethin lestradiol: DMFs
`(”man—d (m4)
`Norethidrone acetate: DMFs (m4) and
`"M”
`Ethinylestradiol: DMFs “M" and 0“"
`
`_-
`Does-the section contam a
`X
`descnptron of the DS
`manufac
`.
`. rocess?
`Does the section contain
`
`13.
`
`identification and controls of
`critical steps and intermediates
`of the DS?
`
`I Doesthesectroncontam
`
`Information regarding the
`characterization of the DS?
`15 Does the section contain
`'
`controls for the DS?
`fisnsfizgizggatfig $313,515
`p
`g
`substance?
`
`Does the application contain
`17. Quality by Design (QbD)
`information re . ardin the DS?
`
`Does the application contain
`Process Analytical
`Technology (PAT)
`information re ardin the DS?
`
`Reference ID: 32231 02
`
`

`

`E. DRUG PRODUCT P
`
`__
`Is there a description of
`manufacturing process and
`methods for DP production
`through finishing. including
`formulation, filling, labeling
`and acka--in?
`
`
`
`Cross reference to NBA 22501
`
`12 month expiry requested based on 6 months
`.
`of data provrded.
`
`X
`
`X
`
`Not a filing issue
`
`.
`.
`Not a filmg lssue
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`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
`a licable?
`
`Is there a batch production
`record and a proposed master
`batch record?
`
`Has an investigational
`formulations section been
`
`provided? Is there adequate
`linkage between the
`investigational product and the
`to osed marketed roduct?
`
`re I uested?
`Does the section contain
`
`description of to-be-marketed
`.
`contamer/closure system and
`resentations)?
`Does the section contain
`
`21.
`
`22
`
`'
`
`24.
`
`25.
`
`controls of the final drug
`roduct?
`
`Has Stab‘llty data and analysrs
`26. been provrded to support the
`.
`.
`re u uested ex rratlon date?
`
`Does the application contain
`27. Quality by Design (QbD)
`information re - ardin the DP?
`
`Does the application contain
`Process Analytical
`28. Technology (PAT)
`information re - ardin the DP?
`
`Reference ID: 32231 02
`
`

`

`F. METHODS VALIDATION (MV)
`
`2- Is there a methods validation
`
`n-ackae?
`
`X
`
`G. MICROBIOLOGY
`
`__
`If appropriate is a separate
`microbiological section
`included assuring sterility of
`
`t—hedl'll' roduct?
`
`_—
`
`H. MASTER FILES
`
`Is information for critical
`
`DMF references (1. e. for drug
`substance and imponant
`packaging components for
`non-solid—oral drug products)
`com 1 lete?
`
`
`
`
`
`(5X
`
`
`
`H—OLDERITEM REFERENCED LOA DATE COMNIENTS
`
`07—Jun-2012
`
`Norethindrone Acetate
`
`07—Jun—2012
`
`M" Speannent Flavor
`
`19-Apr-2010
`
`18-Sep-2008
`
`ADEQUATE °“
`28-Apr-2011. No
`udates.
`
`ADEQUATE on
`14-Jun-2012. No
`udates.
`
`ADEQUATE on
`10-May-2012. N0
`udates.
`
`ADEQUATE 011
`11-Jun-2010. N0
`11 dates.
`
`ADEQUATE on
`07-Dec-2009.
`See 0NDC Policies
`on Bottles and
`Blisters*
`
`15-Sep—2008
`
`ADEQUATE on
`12-Mar-20 l 0.
`
`Ethinyl estradiol
`
`Jul-2011
`
`ADEQUATE 011
`05-Sep-2012. No
`udates.
`
`*Poliq' on the Review ofContainer Closure Systemsfor Solid Oral Drug Products (Bottles), 26--Apr-2001
`Polity on the Review ofBlister Container Closure Systemsfor Oral Tablets and Hard Gelatin Capsules, 29-1May-2002
`
`1 0-Apr-20 12
`
`ADEQUATE on
`1 6-Jun-201 l .
`
`Reference ID: 32231 02
`
`

`

`I. LABELING
`
`been rovided?
`
`Has the draft package insert I
`Havetheinnnediatecontainer I
`
`and carton labels been
`u rovided?
`
`33
`
`
`
`
`
`FILING CONCLUSION
`
`IS THE PRODUCT
`
`THE APPLICATION
`
`FILEABLE?
`If the NDA is not fileable
`
`from the product quality
`perspective. state the reasons
`and provide filing comments
`to be sent to the A licant.
`
`X
`
`N/A
`
`ArethereanypmmfialI—I—review issues to be forwarded
`
`to the Applicant for the 74-
`da letter?
`
`Seen ended electronic Si mture a e
`
`
`Domla F. Christner. Ph.D.
`CMC Lead
`
`Division of New Drug Quality Assessment 11
`Office of New Drug Quality Assessment
`
`{See aQQended electronic sigzmture page}
`
`Moo-Jhong Rhee. Ph.D.
`Chief. Branch IV
`
`Division of New Drug Quality Assessment [1
`Office of New Drug Quality Assessment
`
`Reference ID: 32231 02
`
`Date
`
`Date
`
`

`

`
`
`
`
`
`Attachment A: Nanotechnology product evaluating questions:
`
`1, This review contains new information added to the table below: _______Yes; ___x____No
`Review date: 16-Oct-2012_____________
`
`2) Are any nanoscale materials included in this application? (If yes, please proceed to the next questions.)
`Yes______;
`No______ ; Maybe (please specify)____________________
`
` 3
`
` a) What nanomaterial is included in the product? (Examples of this are listed as search terms in
`Attachment B.) _______________________________________________________________
`
` 3
`
` b) What is the source of the nanomaterial?________________________________________
`4) Is the nanomaterial a reformulation of a previously approved product?
`
`Yes_________ No_________
`5) What is the nanomaterial functionality?
`Carrier_________________; Excipient__________________; Packaging________________
`API____________________; Other____________________
` ____________________________________________________________________________
`6) Is the nanomaterial soluble (e.g., nanocrystal) or insoluble (e.g., gold nanoparticle) in an aqueous
`environment?
`Soluble __________________; Insoluble___________________
`
`7) Was particle size or size range of the nanomaterial included in the application?
`Yes_______(Complete 8); No________ (go to 9).
`
`8) What is the reported particle size?
`Mean particle size___________ ; Size range distribution___________; Other________________
`
`9) Please indicate the reason(s) why the particle size or size range was not provided:
`______________________________________________________________________________
`______________________________________________________________________________
`
`10, What other properties of the nanoparticle were reported in the application (See Attachment E)?
`_______________________________________________________________
`
`11) List all methods used to characterize the nanomaterial?_____________________________
`______________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3223102
`
`10
`
`

`

`
`
`Review Notes
`
`
`
`The applicant has provided the following information on their drug product. It is highlighted in
`blue below. The bioavailability studies were performed under IND 73510.
`
` The proposed regimen and daily doses of active ingredients, and consequently the exposure
`to norethindrone and EE for
` is the same as the approved regimen for Warner
`Chilcott’s Lo Loestrin® Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl
`estradiol tablets and ferrous fumarate tablets) in which all 28 tablets are swallowed. The
`1/10 chewable tablet formulation was based on the approved formulation for Lo
`Loestrin Fe 1 mg NA/10 mcg EE tablets (referred to in the NDA as WC3016 1/10 tablets or
`by its formulation WC3016
` tablets); a flavor
` were added to
`
`1/10 chewable tablets. The WC3016 EE10 tablets are identical to Lo Loestrin Fe 10 mcg EE
`tablets. Lo Loestrin Fe received approval as an oral contraceptive on October 21, 2010 under
`NDA 022501. Reference is made therefore to NDA 022501 in support of the safety and
`efficacy of NA and EE in the prevention of pregnancy (see Section 1.4.4 Cross Reference to
`Other Applications).
`The Application provides comparative bioavailability data from Study PR-12111.
`
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`Reference ID: 3223102
`
`11
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`DRUG SUBSTANCES
`
`The drug product contains two drug substances: Norethindrone acetate and Ethinyl estradiol.
`Full information on the drug substances are provided in the following DMFs:
`
`Norethidrone acetate: DMFs
`Ethinyl estradiol: DMFs
`
`"M"
`
`(IN!)
`
`The following general information is provided in the NDA.
`
`ETHINYL ESTRADIOL
`
`Ethinyl estradiol is sourced from either
`Full information is provided in the cross-referenced DMFs.
`
`on»
`
`0H
`
`
`
`The following tests are performed by Warner Chilcott on Ethinyl estradiol sourced from
`(but) The testing schedule for the API is also provided below.
`5 edfication
`
`Must conform to main] Mott
`WI: to creamy white powder
`
`(5) (4)
`
`Thenolufionisdwmdfitefmm
`
`“solved solid.
`00(4)
`
`
`
`
`SpecificRoIatim
`
`‘" W
`m m
`
`—mwww
`
`Aldldoual Itsls
`
`usr
`
`Identification (TLC)
`
`The cpots ufthe Sample and Standard slmxld
`be sinilarinimensity. sin. shape. cola. and
`R;value
`
`0)“)
`
`Reference ID: 32231 02
`
`12
`
`

`

`
`
`The following tests are performed by Warner Chilcott on Efllinyl estradiol sourced from-
`The testing schedule for the API is also provided below.
`
`
`
`Comment: Information is ad note to allow review. It should be noted that the im
`
`and mum:solventsH
`
`'ties
`
`Reference ID: 3223102
`
`13
`
`

`

`MANUFACTURING
`
`The following sites have manufacturing responsibilities for the Ethinyl Estradiol ding
`substance.
`
`
`
`Comment: EES was submitted on 22-Oct-20] 2 by Kerri-Ann Jennings.
`
`Reference ID: 32231 02
`
`14
`
`

`

`NORETI-IINDRONE ACETATE
`
`Norethindrone acetate is sourced from either
`
`Norethindrone Acetate
`
`The following tests are performed by Warner Chilcott on Norethindrone acetate sourced from
`- The testing schedule for the API is also provided below.
`
`
`
`Reference ID: 32231 02
`
`15
`
`

`

`
`it WT]5|i
`ié
`
`“!
`
`W
`
`E
`
`Reference ID: 3223102
`
`16
`
`The following tests are performed by Warner Chilcott on Norethindrone acetate sourced fi'om
`BSP. The testing schedule for the API is also provided below.
`
`it
`
`E3v
`
`m EP
`E L
`
`ina «may:
`
`

`

`Test Plan
`
`
`
`Comment: Information is adequate to allow review. It should be noted that the impurities
`and residual solvents are diferentfor each supplier based on the synthetic process.
`
`MANUFACTURING
`
`The following sites have manufactun'ng responsibilities for the Norethindrone acetate drug
`substance.
`
`
`
`Comment: EES was submitted on 22-Oct-2012 by Kerri-Ann Jennings.
`
`Reference ID: 32231 02
`
`17
`
`

`

`DRUG PRODUCT
`
`The applicant has provided the following information on the drug product:
`
`-is a 28-mblet oral contraceptive regimen consisting ofthe following (see Figure 1):
`- Twenty-falu-chewable tablets [norethindrone acetate (NA), 1.0 mg and ethinyl
`estradiol (BE). 10 pg per tablet],
`. Two WC3016-ables (EB, 10 pg per tablet),
`0 Two ferrous fumarate tablets. containing 75 mg of ferrous ftmmate per tablet
`The fonnnlation fo_chewable tablets15 based on a previously approved
`formulation, WCSOITLoestrintriniEEA22-501). Themaindifference betweenthe two
`
`blets are intended to be chewable. The WC3016-
`product profiles was that
`blets and the ferrous ftnnarate ta ets are previously approved products in NDA 22-501.
`
`The- 1/10 chewable tablet formulation was based on the approved fornmlation for
`L0 Loestn'n Fe 1 mg NA/10 mc EE tablets (referred to in the NDA as WC3016 l/10 tablets
`gby its formulation WC301
`tablets); a flavor and sweetener were added to
`1/10 chewable tablets. The WC3016 EElO tablets are identical to L0 Lomtn'n Fe 10 mcg EE
`tablets. Lo Loestrin Fe received approval as an oral contraceptive on October 21, 2010 under
`NDA 022501 .
`
`MANUFACTURING SITES
`
`The following sites have manufacttn-ing responsibilities for the drug product:
`
`Establishment and Contact Information - WC-
`
`Nllflnr
`
`Date Illast
`
`FDA“-
`
`WmChikoflCmy,LLC Analytnlmng-Il
`
`‘
`
`_
`
`HeldonulinOpaatiun
`Me: 787 655-8355
`FatMBGS-IIQ'I
`
`70229/2011
`
`baht!
`
`WWWWLW WWII] WWI
`1""thqn'mgn
`bud-1.0mm
`
`Opmtims
`Plume: 0]144-218-2826 7222 at 7215
`Fat 011:45-28-2827-9448
`--
`. can:
`DavidUsslu
`an 353 429395900
`Miami-mom
`
`Comment: EES was submitted on 22-Oct-2012 by Kerri-Ann Jennings.
`
`Reference ID: 3223102
`
`18
`
`

`

`_ chewable tablets (norethindrone acetate 1.0 mg and ethle esIIadiolI 10 meg)
`
`The combination tablets have the following formulation:
`
`Table 1:
`
`Composition of-Chcmblc Tablets
`
`—_\ ll
`—_ II
`Vitamin E (DL-a-Tocophetol)
`Lactose Momhydmte. Past-Flo®
`Norelhindrone Acetate
`Mannitol
`to]
`
`Microcrystalline Cellulose
`
`E
`c:a..1|||iiiiliiiiil
`
`
`mm
`
`—-
`
`MANUFACTURING PROCESS
`
`Reference ID: 32231 02
`
`

`

`
`
`Comment: Information is adequate to allow review.
`
`Reference ID: 32231 02
`
`20
`
`

`

`SPECIFICATION
`
`The combination tablets are controlled with the following specification:
`
`
`__n==-m
`health-MW Whom-24271 WCUK
`mm-fim’mmsfle
`In
`ud‘SSTmllnoln’
`
`W ”Manhattan-hind: Whom-24271 WCUK
`Whhchw-nfixh
`mymfimmeqmdholpoe
`“4&th
`
`[Min-IQ muwduwmh Manchu-24209 WCUK
`WWM)HM
`mung)
`WEE)
`wwmznomouzox Drum-24271 WUK
`dhbeldain
`
`WMM290996”
`110.0%ofldndchim
`
`Drug noon—24122 W UK
`LII:
`
`nugnmamz wcux
`Whom-24043 In:
`
`3.0kpb9.01p
`
`Product-24146 WCUK
`In
`
`2......-Line
`
`W‘ mumdmuz
`Nahum-'(QdMNAuE
`mama-ammo“
`
`human“ wcux
`1-"
`
`
`
`W.0%bllo.0%ofwm mam-24045
`
`USP<61>,USP
`<6»
`
`In
`
`WCUK
`In:
`
`Comments: Specification is based on thatfor the approvedproduct in NBA 2250]. Since these
`are immediate release tablets and the specification is based on an approvedWA, consultation to
`0NDQA BioPharm may not be necessary. It is theprimary reviewer ’s decision on whether a
`BioPharm review is warranted. Information is adequate to allow review.
`
`Reference ID: 3223102
`
`21
`
`

`

`WC3016-(ethinyl eslIadiol 10 mcg)
`
`The ethinyl estIadiol tablets have the following formulation:
`
`Table 1:
`Component
`
`Composition of WC3016—20C Tablets
`Standard
`
`Eminyl Esu'adiol ii
`
`Qulnuty (mg/tablet)
`
`E
`
`p0Vim-=—
`Vitannn E
`
`Lactose Monohydnte,
`Mannitol l
`
`Mlctoctystallme Cellulose
`
`Sodium Scotch Glycolate
`
`Mosulum Stunt:
`
`MANUFACTURING PROCESS
`
`
`
`Reference ID: 32231 02
`
`22
`
`

`

`SPECIFICATION
`
`The cthinyl emadiol tablets have the following specification:
`
`”WWW“ Duncan WCL-ne,
`Mfl‘an-‘hd‘flr‘mh -42
`“pm
`
`Tel She
`
`oh.Uehéw®m
`WCDu-hlk
`unc——m@fin®flnpfi mm
`
`-thmhhmy -42.mfiMMDlnlthln
`WCFj-Ilo
`-_l':mm—42
`
`We! mammals!”
`mm
`(EE)
`
`mm WCLIII,
`-43
`wcrnjmo
`
`hushed-.1 WEI-In,
`-43
`WCP‘
`l
`
`MM WCL-Il,
`'44
`WCF-j-do.
`wcnnnuk
`
`
`
`m—m—
`mam wcL-u.
`-45
`wcrq-m,
`WCDI-hlk
`
`.
`
`‘
`
`some- [Infidmm
`
`“GM mag-no
`use <5»,
`Scan' 111’,
`<5» mm
`In?
`
`Comments: Specification is based on thatfor the approvedproduct in NBA 2250]. Information
`is adequate to allow review.
`
`Reference ID: 3223102
`
`23
`
`

`

`Ferrous fumarate tablets
`
`The composition of the ferrous fumarate tablets is as follows:
`
`Table 1:
`
`Composition of Ferrous anarate Tablets
`
`Quality
`Standard
`
`Quantity
`
`Component
`
`(mg/tablet)
`
`MANUFACTURING PROCESS
`
`The applicant has provided the following flow charts for the manufacturing process. Narratives
`are provided as well.
`
`
`
`Reference ID: 32231 02
`
`24
`
`

`

`SPECIFICATION
`
`The specification for the feuous fumartc tablets is provided below:
`
`MMM‘WC’ momside
`III‘G24’mholu'n’defiee
`
`mum-(momma
`memisissotvedinw
`
`MFolbwhmqnimot
`
`USP<111>
`
`Comments: Specification is based on thatfor the approvedproduct in NBA 2250]. Information
`is adequate to allow review.
`
`Reference ID: 3223102
`
`25
`
`

`

`CONTAINER CLOSURE SYSTEM
`
`The tablets are packaged in the following packaging configuration:
`
`
`
`
`
`The chewable combination tablets are contained in the first 24 wells of the blister pack, while the
`nonchewable ethinyl estradiol tablets are contained in blister wells 25-26 and the inert,
`nonchewable ferrous fumarte tablets are in blister wells 27-28. The blister packaging is the same
`as used in the approved product under NDA 22501.
`
`
`STABILITY
`
`The applicant requests 12 months of expiry based on the following expiry determination for the
`individual tablets:
`
`
`
`
`•
`•
`•
`
`12 months for the combination tablets
`36 months for the EE tablets
`48 months for the ferrous fumarate tablets
`
`
`
`
` (chewable combination tablets)
`
`
`The following stability package was submitted in support of the requested 12 months expiration
`dating period:
`
`
`•
`
`•
`
`•
`
`
`
`Reference ID: 3223102
`
`3 batches of drug product manufactured using
`intermediate and accelerated data
`3 batches of drug product manufactured using
`intermediate and accelerated data
`1 batch for
` 3 months long term, intermediate and accelerated data
`
` 6 months long term,
`
` 3 months long term,
`
`26
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`Comment: Although 6 months of data are less than what is currently recommended by ONDQA,
`based on the fact that the formulation is almost identical to an approved formulation except for
`the addition of
` flavor, and that the applicant requested 12 months of expiration
`dating period, the amount of information is adequate to allow review.
`
`
`WC3016
`
`An expiration dating period of 36 months is supported by the following stability package used to
`support the approved NDA 22501:
`
`
`•
`
`•
`
`5 batches of drug product manufactured with
`stability data
`4 batches of drug product manufactured with
`term stability data.
`
` Up to 48 months of long term
`
` Up to 18 months of long
`
`(ethinyl estradiol 10 mcg)
`
`
`Comment: The amount of data submitted is adequate for review.
`
`Ferrous fumarate tablets
`
`An expiration dating period of 48 months is supported by the following stability package used to
`support the approved NDA 22501:
`
`
`•
`
`8 batches of drug product: Up to 48 months of long term stability data
`
`
`Comment: The amount of data submitted is adequate for review.
`
`
`LABELING
`
`The applicant has provided carton/container labels and a Physician’s Insert. Information is
`adequate to allow review.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3223102
`
`27
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DONNA F CHRISTNER
`11/29/2012
`
`MOO JHONG RHEE
`11/29/2012
`Chief, Branch IV
`
`Reference ID: 3223102
`
`

`

`
`
`Memorandum
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Date: 07/23/2013
`
`From: Gene W. Holbert, Ph.D.
`
`
`
`Senior Review Chemist, ONDQA
`
`
`
`Premarketing Assessment Division II
`
`
` ONDQA
`
`Through: Moo-Jhong Rhee, Ph.D.
`
`
` Chief, Branch IV
`
`
`
`Premarketing Assessment Division II
`
`
` ONDQA
`
`To: CMC Review #1 of NDA 204654
`
`Subject: Approval Recommendation
`
`When CMC review #1 was filed, two issues were outstanding, Establishment Evaluation and the
`final package insert.
`
`On 07/09/2013, the Office of Compliance issued an overall “Acceptable” recommendation for
`all facilities involved in manufacturing and testing of the drug substance and drug product (EER
`Summary Report, Attachment 1).
`
`On 07/23/2013 the final package insert was submitted and the revisions are satisfactory from the
`ONDQA perspective (Attachment 2). Final container and carton labels were submitted on
`07/15/2013.
`
`Recommendation: This NDA is now recommended for Approval from the ONDQA
`perspective with an expiration dating period of 12 months.
`
`
`
`
`Reference ID: 3345882
`
`

`

`Attachment 1: Establishment Evaluation Report
`
`Appllmtion:
`
`Org. Code:
`
`Priority:
`
`stamp Date:
`
`PDUFA Date:
`
`Action Goal:
`District Goal:
`
`NDA 204654IOOO
`
`580
`
`5
`
`28-SEP-2012
`
`28-JUL-2013
`
`29-MAY»2013
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Sponsor:
`
`WARNER CHILCOTT
`
`UNION ST RD 195 KM 1.1
`
`FAJARDO, PR 00738
`(5X4)
`
`.
`norethlndroneacetateand ethlnyl e
`
`Brand Name:
`
`Estab. Name:
`
`1")(Qnorethhdroneacetateand ethinyl e
`Generic Name:
`Product Number; Dosage Form; Ingredient; Strengths
`001: TABLET (IMMED/COMP. RELEASE). UNCOATED. CHEWABLE:
`NORETHINDRONE ACETATE; 1M6
`001. TABLET (lMMED/COMP. RELEASE). UNCOATED. CHEWABLE:
`ETHINYL ESTRADIOL' 10MCG
`001; TABLET (lMMED/COMPt RELEASE). UNCOATED. CHEWABLE:
`ETHINVL ESTRADIOL; 10MCG
`001: TABLET (lMMED/COMP. RELEASE). UNCOATED‘ CHEWABLE:
`FERROUS FUMARATE: 75MG
`
`FDA Contacts; G. HOLBERT
`
`K: JENNINGS
`
`P. LUCARELLI
`D. CHRISTNER
`
`Prod Qual Reviewer
`
`Product Quality PM
`
`Regulatory Project Mgr
`Team Leader
`
`(HFD-SBO)
`
`3017961368
`
`3017962919
`
`3017963961
`3017961341
`
`Overall Recommendation:
`
`ACCEPTABLE
`
`on 09dUL-2013
`
`by M. HEAYN
`
`(HFD-320)
`
`3017964753
`
`Establishment:
`
`CFN:
`
`@(9
`
`FEi:
`
`(”(4)
`
`”(4)
`
`DMi' N0:
`
`Responsibilities:
`Profile:
`
`Last Mllgsfongz
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`DRUG SUBSTANCE OTHER TESTER
`CONTROL TESTING LABORATORY
`
`0C RECOMMENDATION
`
`02NOV-2012
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`MDA:
`
`OAI Status:
`
`NONE
`
`July 9, 2013 4:53 PM
`
`FDA Confidential - internal Distribution Only
`
`Page 1 of 4
`
`Reference ID: 3345882
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establlshmmt:
`
` our No:
`
`Mpg;
`
`Responslblltles:
`Profile:
`
`Last Mlestono:
`
`Mllostono Dab:
`
`Doclslon:
`
`Reason:
`
`DRUG SUBSTANCE MANUFACTURER
`NON—STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`0C RECOMMENDATION
`
`02-Nov-2012
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`MDA:
`
`
`
`Establlshrnont:
`
`DI? No:
`
`Rosponslbllths:
`Pmfllo:
`
`Lat Mlgstong;
`Mllostom Data:
`
`Doolelon:
`
`Ruson:
`
`Establishment:
`
`our No:
`
`Rosponslblmos:
`Profllo:
`
`Last mustang:
`
`Milestone Date:
`
`Doclslon:
`
`DRUG SUBSTANC
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`OC RECOMMENDATION
`02-Nov-2012
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`cm: _
`
`
`
`DRUG SUBSTANCE MANUFACTURER
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`0C RECOMMENDATION
`
`26-JUN-2013
`
`ACCEPTABLE
`
`Reason;
`DISTRICT RECOMMENDATION
`
`
`July 9, 2013 4:53 PM
`
`FDA Confidential - Internal chtflbutlon Only
`
`Page 2 of 4
`
`Reference ID: 3345882
`
`

`

`Establshment:
`
`CFN:
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`FEI:
`
`(5X4)
`
`00(4)
`
`00(4)
`
`AADA:
`
`DMF No:
`
`Responslbilltles:
`
`DRUG SUBSTANCE OTHER TESTER
`
`FINISHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`R8850":
`
`0C RECOMMENDATION
`
`027NOV72012
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Establshment:
`
`CFN:
`
`2619635
`
`FEI:
`
`2619635
`
`DMF No:
`
`Responsibllltles:
`
`Profile:
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`PIOTIIOI
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`WARNER CHILCOTI' COMPANY, INC.
`
`FAJARDO. . UNITED STATES 00738
`
`DRUG SUBSTANCE OTHER TESTER
`FINISHED DOSAGE MANUFACTURER
`
`CONTROL TESTING LABORATORIES l'ALSO"
`(DRUGS)
`oc RECOMMENDATION
`
`01 MAY-201 3
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`TABLETS, PROMPT RELEASE
`
`OC RECOMMENDATION
`
`01MAY-2013
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`MDA:
`
`OAI Status:
`
`NONE
`
`OAI status:
`
`NONE
`
`July 9, 2013 4:53 PM
`
`FDA Confldentlal -Intemal Distribution Only
`
`Page 3 of 4
`
`Reference ID: 3345882
`
`

`

`
`
`
`
`
`
`Reference ID: 3345882
`
`
`
`4 Page(s) of Draft Labeling
`have been Withheld in Full as
`b4 (CCI/TS) immediately
`following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`GENE W HOLBERT
`07/23/2013
`
`MOO JHONG RHEE
`07/23/2013
`Chief, Branch IV
`
`Reference ID: 3345882
`
`

`

`
`
`NDA 204654
`
`Trade Name
`
`Norethindrone Acetate and Ethinyl Estradiol
`Chewable Tablets, Ethinyl Estradiol Tablets,
`and Ferrous Fumarate Tablets
`
`1mg/10mcg and 10mcg
`
`Warner Chilcott
`
`Gene W. Holbert, Ph.D.
`
`Senior Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment II
`Branch IV
`
`CMC Review for the
`
`Division of Bone, Reproductive and Urologic Products
`
`Reference ID: 3325983
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
`
`The Executive Summary .........................................................................................7
`
`1. Recommendations ...................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps, if Approvable ................................................................................................... 7
`
`II. Summary of Chemistry Assessments......................................................................................... 7
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 7
`
`B. Description of How the Drug Product is Intended to be Used ......................................................... 8
`
`C. Basis for Not—Approval Recommendation....................................................................................... 8
`
`III. Administrative............................................................................................................................ 9
`
`A. Reviewer’s Signature ....................................................................................................................... 9
`
`B. Endorsement Block .......................................................................................................................... 9
`
`C. CC Block...............................................................................................................................