CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`203752Orig1s000
`
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

` a DEPARTMENT OFHEALTH&HUMAN SERVICES
`
`r
`Food and Dru , Administration
`
`Center for Drug Evaluation and Research
`Division of Pharmaceutical Analysis
`St. Louis, MO 63101
`
`Tel. (314) 539-3874
`
`Date:
`
`October 12. 2012
`
`To:
`
`Caroline Strasinger. Review Chemist. ONDQA
`
`Through:
`
`Benjamin Westenberger, Deputy Director. Division of Pharmaceutical Analysis
`
`From:
`
`Anna Wokow'ch. Chemist. Division of Pharmaceutical Analysis
`
`Subject:
`
`Crystal formation of
`
`“""Estradiol TDDS with elevated humidity
`
`Objective:
`To determine if crystals form when the
`elevated humidity.
`
`M“) estradiol transdermal drug delivery system is exposed to
`
`Background:
`ONDQA Review Chemist. Dr. Caroline Strasinger, submitted a Methods Validation Request for NDA 203-752.
`Noven Pharmaceuticals’s
`“M" (Estradiol Transdermal System). The requested determinations were for
`Release Liner Peel Force, Shear Adhesion. Peel Adhesion. Probe Tack, and Cold Flow. Additionally, Dr.
`SlIasinger requested that samples (opened and with adhesive matrix exposed) be placed in a humid enviromnent
`for 2-5 days and examined for crystals using a microscope.
`
`Conclusions:
`
`No crystals were observed for the ambient Day 1- Day 4 samples with their release liners on and off. No crystals
`were observed for the chamber (32°C and 75% RH) Day 1- Day 4 samples with their release liners on and 011‘.
`Also, no crystals were observed for the chamber Day 1 - Day 4 samples that were in their intact pouches before
`opening.
`
`Samples/Materials:
`NDA samples of 6.6 cm2, 3.3 cm2, 2.475 cm2, and
`systems. (See Attachment A.)
`
`(m4)
`
`(mu) estradiol transdermal
`
`Experimental/Methods:
`For each dosage, systems removed from their pouches with their release liners intact, systems removed fiom their
`pouches with their release liners removed and systems in their intact (sealed) pouches were placed in an
`environmental test chamber at 32°C and 75% relative humidity for 4 days. Also, systems in their intact (sealed)
`pouches were placed on the lab bench at ambient conditions.
`
`DPATR—FY13—004
`
`Page 1 of 4
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`Reference ID: 3202366
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`Each test day, the designated samples were removed from the chamber as well as the designated ambient samples
`and examined for crystals macroscopically and microscopically. (See Attachment A.) After examination, the
`samples were returned to their storage conditions.
`
`
`Results/Discussion:
`Ambient conditions ranged from 17°C-22°C and 42%-66% relative humidity (RH), and the environmental test
`chamber was set to 32°C and 75% RH. No crystals were observed for the ambient Time 0, Day 1, Day 2, Day 3,
`and Day 4 samples with their release liners on and off. No crystals were observed for the chamber Day 1, Day 2,
`Day 3, and Day 4 samples with their release liners on and off. No crystals were observed for the chamber Day 1,
`Day 2, Day 3, and Day 4 samples that were in their intact pouches before opening. For the samples that had their
`release liners off, some dirt/threads from the air adhered to the adhesive. (See Attachment B.)
`
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`DPATR-FY13-004
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`Reference ID: 3202366
`
`Page 2 of 4
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`2 Page(s) has 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/
`----------------------------------------------------
`
`MICHAEL L TREHY
`10/11/2012
`
`Reference ID: 3202366
`
`

`

`NDA 203752
`ADDENDUM
`
`Minivelle (estradiol transdermal system)
`
`
`Noven Pharmaceuticals Inc.
`
`
`
`Caroline Strasinger, Ph.D.
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment II
`Branch IV
`
`
`
`CMC Review of NDA 203752
`For the Division of Reproductive and Urological Products
`
`
`
`
`Reference ID: 3194443
`
`

`

`Chemistry Review Data Sheet
`
`
`
`
`1. NDA
`
`2. REVIEW #:
`
`
`3. REVIEW DATE:
`
`
`4. REVIEWER:
`
`5. PREVIOUS DOCUMENTS:
`
`
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`203752
`
`#2
`
`25-SEP-2012
`
`Caroline Strasinger, Ph.D.
`
`Previous Documents
`Quality Review #1
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`Amendment 0010
`Amendment 0011
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`
`30-AUG-2012
`
`Document Date
`17-SEP-2012
`19-SEP-2012
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`Noven Pharmaceuticals, Inc.
`Empire State Building
`350 Fifth Avenue, 37th Floor
`New York, NY 10118
`Sean M. Russell, Associate Director, Regulatory
`Affairs
`212-299-4208
`
`
`
`
`
`Reference ID: 3194443
`
`

`

`The Chemistry Review for NDA 203752
`The Executive Summary
`I. Synopsis of Information
`
`
`Several clarifications were required regarding the Applicant’s commitment to qualify
`a more distinguishable ink (
` provided to the NDA on 27-AUG-2012 and
`previously discussed in Review #1.
`
`
`In summary, the Applicant will launch their commercial product utilizing
` ink and continue to utilize
` ink while completing their qualification and
`stability work of the more distinguishable ink. The Applicant confirmed they do not
`intend to switch between
` and
` based on the concern for
`potential patient confusion.
`
`II. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`This NDA has provided sufficient information to assure the identity, strength, purity,
`and quality of the drug product.
`
`The Office of Compliance has issued an “ACCEPTABLE” overall recommendation
`on all the manufacturing facilities.
`
`The labels/labeling have adequate information.
`
`Therefore, from the ONDQA perspective, this NDA is recommended for approval.
`
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`
`
`None
`
`
`Reference ID: 3194443
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Chemist_rg Assessment
`
`Background
`NDA 203752 which provides for the Minivelle (estradiol transdermal system) was
`originally submitted 29-DEC-2012.
`
`This addendum to the Quality Review dated 30-AUG-2012 addresses the following:
`
`(m4)
`(m4) versus
`0 An assessment of the risk of using the ink
`including a summary of extractables and leachables testin as well as an up dated
`Letter of Authorization (LoA) to reference the
`(m ) ink.
`
`0 Clarifications regarding the use of
`launch and during the qualification period.
`
`mm) versus
`
`(m4) at product
`
`Assessment of Risk
`
`The Applicant provided information in amendments dated 17—SEP—2012 and l9—SEP—
`2012 demonstrating that the change in ink from
`M“) to
`M“) is not of
`significant risk to implement. The applicant provided and updated LoA to reference the
`appropriate inks in DMF
`(m4) and stated that
`(no)
`Additionally, the applicant provided a smnmary of
`extractable and leachable testing of systems printed with
`(m4) and no peaks were
`detected above the LOQ of :2} ppm.
`
`(hm) improves the readability of the identifying label.
`Reviewer Evaluation:
`Based on the risk analysis provided by the Applicant, implementing
`(mo in
`the manufacturing process does not present a safety risk nor is it considered a major
`amendment to Application. The Applicant has committed to conducting concurrent
`stability studies to qualify the
`(mm as indicated in the amendment
`dated 27-AUG—2012.
`
`Clarification
`In a teleconference on 20-SEP-2012 it was confmned that
`
`(hm) ink would be used
`
`to print the identifying label on the transdermal system at product launch, once the
`product is branded
`(m4) and during the on-going
`qualification and stability assessment of
`"W" The Applicant confmned they do
`not intend to switch between
`(m4) and
`M“) based on the concern for
`
`potential patient confusion despite both inks being approved for use.
`
`Reviewer Evaluation: The information is adequate.
`
`Reference ID: 31 94443
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CAROLINE STRASINGER
`09/25/2012
`
`TERRANCE W OCHELTREE
`09/28/2012
`
`Reference ID: 3194443
`
`

`

`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`METHODS VALIDATION REPORT SUMMARY
`
`TO:
`
`
`
`
`Caroline Strassinger, CMC Reviewer
`Office of New Drug Quality Assessment (ONDQA)
`E-mail Address: caroline.strassinger@fda.hhs.gov
`Phone: (301)-796-3776
`Fax:
`(301)-796-9877
`
`FROM: FDA
`
`Division of Pharmaceutical Analysis
`Michael Trehy, MVP Coordinator
`Suite 1002
`1114 Market Street
`St. Louis, MO 63101
`Phone: (314) 539-3815
`
`
`
`
`Through: Benjamin J. Westenberger, Deputy Director
` Phone: (314) 539-3869
`
`SUBJECT: Methods Validation Report Summary
`
`
`
`Application Number: 203-752
`
`
`
`
` (Estradiol transdermal System);
`Name of Product:
`Applicant: Noven Pharmaceuticals, Inc.
`Applicant’s Contact Person: Sean M. Russell
`Address: 350 Fifth Avenue, 37th Floor, New York, NY 10118
`
`, 0.0375, 0.05, 0.075, 0.1 mg/day
`
`Telephone: (212) 229-4208
`
`
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`Fax: NA
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`Date Methods Validation Consult Request Form Received by DPA: 5/7/2012
`Date Methods Validation Package Received by DPA: 5/7/2012
`
`Date Samples Received by DPA: 7/3/2012
`Date Analytical Completed by DPA: 9/19/2012
`
`Laboratory Classification: 1. Methods are acceptable for control and regulatory purposes.
`
`2. Methods are acceptable with modifications (as stated in accompanying report).
`
`3. Methods are unacceptable for regulatory purposes.
`
`
`
`Comments:
`
`See attached memo for analyst’s comments.
`
`DPATR-FY12-116
`
`
`Reference ID: 3192302
`
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`Page 1 of 7
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`Version: 7/13/2011
`
`(b) (4)
`
`(b) (4)
`
`

`

` a DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`r
`Food and Dru Administration
`
`Center for Drug Evaluation and Research
`Division of Pharmaceutical Analysis
`St. Louis. MO 63101
`
`Tel. (314) 539-3874
`
`Date:
`
`To:
`
`September 20. 2012
`
`Dr. Caroline Strasinger, Reviewer, Office of New Drug Quality Assessment
`
`Through:
`
`Benjamin Westenberger, Deputy Director, Division of Pharmaceutical Analysis
`
`From:
`
`Anna Wokovich. Chemist, Division of Pharmaceutical Analysis
`
`Subject:
`
`Method Validation for NDA 203-752
`NDA 203-752,
`0"" transdennal drug delivery system
`Probe Tack. Peel Adhesion, Release Liner Peel Force, Cold Flow, and Shear Adhesion
`
`The following methods were evaluated:
`Probe-Tack Test for Transdermal Systems GDOCUMENT NO STP-QC-0516 REVISION 1
`EFFECTIVE DATE 16 MAR 2012)
`
`Peel Adhesion Test for Transdermal Systems (DOCUMENT NO ST‘P-QC-0514 REVISION 2
`EFFECTIVE DATE 29 MAR 2012)
`
`Determination of the Peel Force from Release Liner for Transdermal Systems with small Area- Peel
`from Liner Test (DOCUMENT NO STP 412 REVISION 2 EFFECTIVE DATE 29 MAR 2012)
`
`Cold Flow Test (DOCUMENT NO STP-QC-0515 REVISION 1 EFFECTIVE DATE 16 MAR 2012: Cold
`Flow test for Transdermal Systems)
`
`Shear Adhesion of Transdermal Systems with Small Area— Shear Test O)OCUMENT NO STP 411
`REVISION 3 EFFECTIVE DATE 14 MAR 2012)
`
`The following methods are acceptable for quality control and regulatory purposes:
`Probe-Tack Test for Transdermal Systems (DOCUMENT NO STP-QC-0516 REVISION 1
`EFFECTIVE DATE 16 MAR 2012)
`
`The following method was evaluated and is acceptable for quality control and regulatory purposes with
`modification:
`
`Peel Adhesion Test for Transdermal Systems (DOCUMENT NO STP-QC-0514 REVISION 2
`EFFECTIVE DATE 29 MAR 2012)
`
`5 Page(s) has been Withheld in Full as B4 (CCIITS) immediately following this page
`
`DPATR-FYIZ-l 16
`
`Page 2 of 7
`
`Version: 7/13/2011
`
`Reference ID: 31 92302
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MICHAEL L TREHY
`09/20/2012
`
`BENJAMIN J WESTENBERGER
`09/21/2012
`
`Reference ID: 3192302
`
`

`

`
`
`NDA 203-752
`
`Minivelle (estradiol) Transdermal System
`
`Noven Pharmaceuticals, Inc.
`
`Caroline Strasinger, Ph.D.
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment II
`Branch IV
`
`CMC Review of NDA 203-752
`
`For the Division of Reproductive and Urological Products
`
`Reference ID: 3181383
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`I. 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 Approvability or Not-Approval Recommendation ............................................................ 8
`
`III. Administrative........................................................................................................................... 8
`
`A. Reviewer’s Signature ........................................................................................................................ 8
`
`B. Endorsement Block........................................................................................................................... 9
`
`C. CC Block .......................................................................................................................................... 9
`
`Chemistry Assessment ........................................................................................... 10
`
`1. Review Of Common Technical Document—Quality (Ctd—Q) Module 3.2: Body Of Data ....... 10
`
`s DRUG SUBSTANCE [EsIIadioL
`
`“("1 ................................................................................. 10
`
`P DRUG PRODUCT [Minivelle, Transdennal System] ................................................................. 17
`
`A APPENDICES .............................................................................................................................. 67
`
`R REGIONAL INFORMATION ..................................................................................................... 68
`
`II. Review Of Common Technical Document-Quality (Ctd—Q) Module 1 ..................................68
`
`A. Labeling & Package Insert ............................................................................................................ 68
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................... 78
`
`111.
`
`List Of Deficiencies To Be Communicated ....................................................................... 79
`
`Reference ID: 3181383
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA
`
`2. REVIEW #:
`
`203-752
`
`#1
`
`3. REVIEW DATE:
`
`August 20, 2012
`
`4. REVIEWER:
`
`Caroline Strasinger, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`N/A
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissions 3 [ Reviewed
`Original
`Amendment 0002
`
`Amendment 0005
`
`Amendment 0006
`
`Amendment 0007
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`29-DEC-201 l
`
`27—APR—2012
`
`15-JUN-2012
`
`02-JUL-2012
`
`31-JUL-2012
`
`Name:
`
`Address:
`
`Noven Pharmaceuticals, Inc.
`
`Empire State Building
`350 Fifth Avenue, 37th Floor
`New York, NY 10118
`
`Representative:
`
`Sean M. Russell, Associate Director
`
`Telephone:
`
`212-299-4208
`
`Reference ID: 3181383
`
`Page 3 of 84
`
`

`

`
`
`Chemistry Review Data Sheet
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):
`c) Code Name/#: N/A
`(1) Chem. Type/Submission Priority:
`
`0 Chem. Type: 3
`
`0 Submission Priority: Stande
`
`Minivelle
`estradiol transdermal system
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`505 (b)(1)
`
`10. PHARMACOL. CATEGORY: Steroid hormones
`
`11. DOSAGE FORM:
`
`Transdermal System
`
`12. STRENGTH/POTENCY:
`
`"”“’, 0.0375, 0.05, 0.075, 0.1
`mg/day;
`
`13. ROUTE OF ADMINISTRATION:
`
`Transdermal
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM ):
`
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Estradiol:
`
`Estra—l,3,5(10)—t1iene—3,17—diol, (l7|3)
`
`Molecular Formula: C13H2402
`
`Molecular Weight: 272.38
`
`Reference ID: 3181383
`
`Page 4 of 84
`
`

`

`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`STATUS2
`
`DATE
`
`REVIEW
`COMPLETED
`
`COMMENTS
`
`Adequate
`
`-- m
`
`Dr. S. Dhanesar
`
`
`
`
`
`
`
`for NDA 203752
`
`Adequate
`
`Dr. R. Shaltnaz for
`ANDA
`"M"
`
`
`4/25/2011
`
`N/A
`
`06/14/2005
`
`for NDA 203—752
`Dr. D. Klien for
`
`NDA
`
`(5)“)
`
`
`
`
`11/30/2011
`
`for NDA 203752
`Dr. X L1 for
`
`
`
`1Action codes for DMF Table:
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previome and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents:
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`20-323
`
`Vivelle®
`
`Reference ID: 3181383
`
`Page 5 of 84
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`

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`
`
`Chemistry Review Data Sheet
`
`18. STATUS:
`
`CONSULTS/ CMC
`
`RELATED
`
`REVIEWS
`
`RECONINIENDATION
`
`DATE
`
`————
`
`
`
`_———
`Methods Validation
`To be done per
`Pending
`ONDQA’s policy
`Submitted 7-MAY-2012
`
`DMEPA_Claimforcategorical
`_exclusion15 u anted
`
`
`
`1—5—FEB-2012C—arolineStrasinger,PhD.
`
`Microbiology ———
`
`Reference ID: 3181383
`
`Page 6 of 84
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`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 203-752
`
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The Applicant of this NDA has provided sufficient information to assure the identity,
`strength, purity, and quality of the drug product.
`
`The Office of Compliance has issued an overall “Acceptable” recommendation for the
`facilities involved in the NDA. The labels have adequate information as required.
`
`Therefore, from the ONDQA perspective, this NDA is recommended for approval.
`
`. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`No CMC related Phase 4 are proposed at this time.
`
`H. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Substance:
`The drug substance, estradiol, is a white to practically white crystal or powder with a
`melting point of l73-179°C. It has an empirical formula of C18H2402 and a molecular
`weight of 272.38. The drug substance will be manufactured and packaged at
`:2;
`
`4
`-
`M”
`The drug substance contams
`no changes
`In 30 years of manufacturing experience at
`(hm) have arisen. Estradiol is used in several currently
`affecting
`approved FDA products including the referenced NDA 20-538 for Vivelle-Dot. The
`applicant
`references DMF
`(am)
`for all
`relevant
`information pertaining to the
`manufacture, control and release of the drug substance. DMF M“) was most recently
`reviewed and deemed adequate on 24-MAY-2011; no changes to the DIVIF have been
`made since this review, therefore DMF m4) is deemed adequate to support NDA 203-
`752.
`
`“" Fl
`
`Drug Product:
`Minivelle is a transdennal drug delivery system (TDDS) designed to continuously
`release l7B-estradiol when applied to intact skin. mu) systems are proposed for market
`in this application ranging in strength from (m4) mg/day to 0.1 mg/day containing mm
`
`Reference ID: 3181383
`
`Page 7 of 84
`
`

`

`
`
`Executive Summary Section
`
`mg to 1.65 mg estradiol. Minivelle has the same multipolymeric adhesive platform as
`the currently marketed Vivelle-Dot and has a been designed to deliver the same
`therapeutic levels of estradiol as Vivelle and Vivelle—Dot, but from a smaller active
`surface area. The TDDS are circular in shape and translucent to slightly opaque white.
`The TDDS is manufactured at Noven Pharmaceuticals in Miami, FL. Two additional
`facilities have been listed for raw material and finished product microbial testing all of
`which are domestic. It was noted during review, that the maximum storage time for the
`raw material
`(m4) is
`M“) from the date of manufacture. Use within iii
`(prevents the impurity
`(m4) from rising above USP acceptance criterion of
`)
`
`(b)
`
`The quality of the drug product is controlled by tests for appearance, assay, content
`uniformity, identification, adhesion, drug release, impurities, cold flow, pouch seal
`integrity and microbial limits. Each carton will contain eight TDDS of one strength. A
`24 month expiration date has been granted based on 12 months of provided stability
`data and supporting Vivelle-Dot data.
`
`B. Description of How the Drug Product is Intended to be Used
`Minivelle (estradiol)
`M“) 0.0375, 0.05, 0.075, 0.1 mg/day is a multipolymeric
`adhesive system that releases estradiol continuously upon application to intact skin for
`the treatment of severe vasomotor symptoms associated with menopause. The adhesive
`side of Minivelle should be placed on a clean, dry area of the trunk of the body
`(including the adbdomen or buttocks). Minivelle should not be applied to the breast.
`The transdermal delivery system is designed for continuous wear with application of a
`new system twice weekly to a different site with each application. The product should
`be stored at room temperature.
`
`. Basis for Approvability or Not-Approval Recommendation
`From the ONDQA perspective, this NDA is recommended for Approval.
`
`information on raw material controls,
`The Applicant has provided sufficient
`manufacturing processes and process controls, and adequate specifications for assuring
`consistent product quality of the drug substance and drug product. Also sufficient
`stability information is provided on the drug product in the NDA to assure strength,
`purity, and quality of the drug product during the expiration dating period (24 months).
`
`Office of Compliance has issued an “Acceptable” overall recommendation for all
`facilities involved.
`
`Labels/labeling have the required information.
`
`111. Administrative
`
`A. Reviewer’s Signature
`
`Reference ID: 3181383
`
`Page 8 of 84
`
`

`

`
`
`Executive Summary Section
`
`B. Endorsement Block
`
`Chemist Name/Date: Caroline Strasinger, PhD 27-AUG-2012
`ChemistlyTeamLeaderName/Date: Donna Christner, PhD; 27-AUG-2012
`ProjectManagerName/Date: Rebecca McKnight; 27-AUG-2012
`
`C. CC Block
`
`
`
`Reference ID: 3181383
`
`Page 9 of 84
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CAROLINE STRASINGER
`08/30/2012
`
`TERRANCE W OCHELTREE
`08/30/2012
`
`Reference ID: 3181383
`
`

`

`Initial Quality Assessment
`Branch IV
`
`Division of New Drug Quality Assessment II
`
`0ND Division: Division of Reproductive and Urologic Products
`NBA:
`203 752
`
`Applicant: Noven Pharmaceuticals
`Stamp Date:
`29-Dec-20] 1
`PDUFA Date:
`29-Oct-2012
`Trademark:
`0M4)
`Established Name: Estradiol
`
`Dosage Form: Transdermal system
`Route of Administration: Transdermal
`
`Indication: Treatment of VMS
`
`CMC Lead: Donna F. Christner, Ph.D.
`
`ONDQA Fileability: X
`Comments for 74-Day Letter X
`
`[I
`E]
`
`YES NO
`
`Summary and Critical Issues:
`
`A. Summary
`
`The drug product is a translucent, round, estradiol trandermal system available in :2} sizes
`as follows, with the following estradiol concentrations. The patch is applied twice
`weekly.
`
`Table 2:
`
`Strengths of Estradiol Transdermal System
`
`Patch Size
`
`Estradiol Concentration
`in Adhesive Blend
`
`Estradiol Content per
`l'nit
`
`Strength
`
`0.0375 mg/day
`
`2.48 cm2
`
`0.62 mg
`
`3.30 cm2
`
`4.95 cm2
`
`6060 cm2
`
`0.05 mgr'day
`
`0075 mgf'day
`
`0.1 lug/day
`
`Each transdermal system is composed of three layers as follows:
`
`Reference ID: 3092318
`
`

`

`Proceeding from the visible surface toward the surface attached to the skin. these layers are:
`
`lb) (4)
`
`Layer 1:
`
`Layer 2:
`
`Layer 3:
`
`“Wprinted backing film.
`
`The active layer consisting of an acrylic adhesive. silicone adhesive. oleyl
`alcohol. povidone. dipropylene glycol and estradiol. with a
`((2; mg cm‘
`coat weight.
`
`“mpolyester
`
`.
`m“) release liner.
`
`4
`tb)( )
`
`lb) (4)
`
`Each estradiol transdermal system is sealed in one pouch. There are two different pouch sized to
`accommodate difi‘erent patch sizes. Patches are provided in “Calendar Packs” of 8 systems and in
`cartons containing 3 “Calendar Packs.”
`
`B. Critical issues for review
`
`The applicant has performed a pivotal bioequivalence study, N28-004. which evaluated the
`highest dosage strength of
`m4) of 1.65 mg estradiol/6.6 cm2 (0.] mg/day). They have also
`provided a supportive dose-proportionality study, N28—005, on three dosed of
`mm
`mm)
`0.827 mg estradiol/3.3 cm2, and 1.65 mg estradiol/6.6 cm2 patches. They are
`requesting a biowaiver of the lower dosage strengths. Tapash Ghosh, Ph.D. has been assigned to
`address all BioPharmaceutic issues.
`
`The applicant has used a bracketing design for their stability studies, since the different strengths
`are the same formulation and differ only by the size of the patch cut from the roll. This will
`require careful review.
`
`C. Comments for 74-Day Letter
`
`See ATTACHMENT 1 for comments to be conveyed to the sponsor.
`
`D. Recommendation:
`
`This NDA is fileable from a CMC perspective. Caroline Strasinger, PhD. is the primary CMC
`reviewer. Tapash Ghosh, Ph.D. is the assigned BioPharm reviewer.
`
`REGULATORY BRIEFING RECOMMENDATION: Branch-level. since the formulation is
`
`highly similar to the approved Vivelle-Dot patch.
`
`Donna F. Christner. Ph.D.
`
`Reference ID: 3092318
`
`

`

`NDA Number: 203752
`
`Type: 5
`
`Established/Proper Name:
`estradiol transdermal system
`
`Applicant: Noven
`_
`.
`Pha1 macentlcals
`
`Letter Date: 29—Dec—2011
`
`Stamp Date: 29—Dec—2011
`
`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
`
`11 IsWW Il—adeuatel
`
`1
`
`Is the CMC section indexed
`
`2.
`
`and paginated (including all
`PDF files) ade uatel ?
`
`X
`
`Are all the pages in the CMC
`section le- 'ble?
`
`Has all information requested
`dining the IND phase and at
`the pre-NDA meetings been
`inc—luded9
`
`
`
`FACILITIES“
`
`Drug substance information15 provided1n
`
`Module 3
`
`Drug product informationrs provided as
`attachment to 356h andm Module 3
`
`i
`
`Is a single comprehensive list
`
`of all involved facilities
`
`availablein one locationin the
`a 1 lication?
`
`For a naturally-derived API
`only are the facilities
`responsible for critical
`intermediate or crude API
`
`manufacturing or performing
`upstream steps specifiedin the
`application? Ifnot has a
`justification been provided for
`this omission9 This question
`is not applicable 1‘01
`synthesized API.
`
`Reference ID: 3092318
`
`

`

`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
`
`
`
`Information provided in Module 3
`
`X
`
`
`
`Information provided on attachment to 356h
`
`Reference ID: 3092318
`
`

`

`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.
`
`Information provided 011 356h
`
`
`
`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
`
`__
`
`u rovided? Has an environmental
`
`assessment report or
`categorical exclusion been
`
`X
`
`Categorical exclusion requested as per 21
`CFR 25.31(b) and 25.15(a)
`
`Reference ID: 3092318
`
`

`

`D. DRUG SUBSTANCE/ACTIVE PHARMACEUTICAL INGREDIENT IS/AP
`
`_-
`Does the section contain a
`description of the DS
`manufacturin‘ rocess?
`Does the section contain
`
`12.
`
`X
`
`Cross-reference to DMF (m4)
`
`Cross-reference to DMF (m4)
`
`Cross-reference to DMF (m4)
`
`_
`
`identification andcontrols.Of
`critical steps and intermediates
`of the DS?
`Does the section contain
`information regarding the
`characterization of the DS?
`
`
`
`13.
`
`X
`
`X
`
`Has stability data and analysis
`
`substance?
`
`17. Quality by Design (QbD)
`information re . ardin. the DS?
`
`Does the application contain
`Process Analytical
`Technology (PAT)
`information re ardin the DS?
`
`X
`
`X
`
`Not a filing issue
`
`.
`.
`Not a filing issue
`
`Reference ID: 3092318
`
`

`

`EE--_-
`
`PlV otal BE study performed usmg highest dosage
`strength of l 65 mg estradiol/6 6 cm (0 1 mg/day)
`Requests biowan er of lower dosage strengths
`0’)
`(4)
`o 0.62 mg/2.48 cm: (0.375 mg/day)
`o 0.83 mg/3.30 cm2 (0.05 mg/day)
`o124m 495cm2 0075m da
`
`Executed batch records are provided.
`Proposed MBR will be requested.
`
`Applicant has used a bracketing desrgn Since the
`fonnulatron and packaging of each patch are the
`same and differ only by the punch srze 24 month
`expiry requested based on 9 months data on three
`batches and reference to V“, elle-Dot dru o roduct
`
`Not a filing issue
`
`Not a filmg issue
`
`E. DRUG PRODUCT
`
`I
`
`Is there a description of
`manufacturing process and
`methods for DP production
`through finishing. including
`formulation, filling, labeling
`and acka - in- ?
`
`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? 15 there adequate
`linkage between the
`investigational product and the
`r0 osed marketed roduct?
`
`Have any biowaivers been
`requested?
`
`Does the section contain
`
`description of to-be-marketed
`container/closure sys