`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203567Orig1s000
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`Memorandum
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`Date:
`To:
`
`From:
`
`Through:
`
`CC:
`
`Subject:
`
`27-May-2014
`CMC Review #2 for NDA 203567
`
`Bogdan Kurtyka, Ph.D.
`CMC Reviewer, ONDQA Division II
`
`Moo-Jhong Rhee, Ph.D.
`Chief, Branch IV ONDQA Division II
`
`Shulin Ding, Ph.D.
`CMC Lead, ONDQA Division II
`
`Final CMC Recommendation
`
`Previous CMC Review #2 dated 08-May-2014 and entered into DARRTS system on 09-May-
`2014 noted the following deficiencies which resulted in the recommendation of “Non Approval”
`action.
`
`1. The Office of Compliance has not issued an overall “Acceptable” recommendation.
`2. Unresolved label/labeling issues
`
`Regarding Item #1:
`On 27-May-2014 the Office of Compliance issued an overall “Acceptable” recommendation
`for establishments (see the Attachment 1).
`
`Regarding Item #2,
`On 16-May-2014 and 23-May-2014, the applicant submitted finalized label/labeling which
`are satisfactory from the ONDQA’s perspective (see the Attachment 2).
`
`Recommendation:
`
`Because these issues were resolved satisfactorily, from the ONDQA perspective, this NDA is
`now recommended for Approval with expiration dating period of 36-month for all
`container/closure configurations.
`
`Reference ID: 3514834
`
`Page 1 of 5
`
`

`

`Attachment 1: EES Summary Report
`
`Reference ID: 3514834
`
`Page 2 of 5
`
`

`

`Establishment:
`
`CFN:
`
`9612799
`
`FEI:
`
`3002807376
`
`DMF No:
`
`Responsibilities:
`
`Profile:
`
`Last Milestone:
`
`Milestone Date:
`
`Decision :
`
`Reason :
`
`Establishment:
`
`DMF No:
`
`Responsibilities:
`Profile:
`
`Last Milestone:
`
`Milestone Date:
`
`Decision :
`
`Reason :
`
`KAKEN PHARMACEUTICAL CO., LTD.
`301 GENSUKE FUJIEDA SHI 426
`
`FUJIEDA-SHI, SHIZUOKA—KEN. JAPAN
`
`DRUG SUBSTANCE RELEASE TESTER
`FINISHED DOSAGE MANUFACTURER
`FINISHED DOSAGE RELEASE TESTER
`
`AADA:
`
`MWLIQUID (OTHER THAN susp a.
`EMULSIONS)
`oc RECOMMENDATION
`
`OAI Status:
`
`NONE
`
`27-MAY-2014
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`CFN:
`
`)—
`(hm
`FEI:
`
`lb)(4)—
`
`(I!) (4)
`
`AADA:
`
`OAI Status:
`
`I‘DNE
`
`FINISHED DOSAGE RELEASE TESTER
`CONTROL TESTING LABORATORY
`
`OC RECOMMENDATION
`
`06-MN-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Establishment:
`
`CFN:
`
`M14)
`
`FEI:
`
`lb)14)—
`mu)
`
`DMF No:
`
`Responsibilities:
`Profile:
`
`Last Milestone:
`
`Milestone Date:
`
`Decision :
`
`Reason :
`
`Establishment:
`
`DMF No:
`
`Responsibilities:
`
`Profile:
`
`Last Milestone:
`Milestone Date:
`Declslon:
`
`Reason:
`
`DRUG SUBSTANCE OTHER TESTER
`
`CONTROL TESTING LABORATORY
`
`OC RECOMMENDATION
`
`1 8—APR—2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`cm: W"
`
`Fa;
`
`(m4)
`
`m4)
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE STABILITY TESTER
`
`(b) “’API BY CHEMICAL SYNTHESIS
`0C RECOMMENDATION
`
`D‘J—MAY»2DI 3
`
`ACCEPTABLE
`
`DISTRICT RECOMMB‘IDATION
`
`AADA:
`
`OAI Status:
`
`NONE
`
`AADA:
`
`OAI Status:
`
`NONE
`
`Reference ID: 3514834
`
`Page 3 of 5
`
`

`

`Attachment 2: Finalized labeling and labels
`
`1. Package Insert
`
`(a) “Highlights” Section
`
`JUBLIA® (efinaconazole) topical solution, 10%
`For topical use
`Initial U.S. Approval: 2014
`
`(b) “Full Prescribing Information” Section
`
`# 3: Dosage Forms and Strengths
`
`JUBLIA (efinaconazole) topical solution, 10% contains 100 mg of efinaconazole in each
`gram of clear, colorless to pale yellow solution.
`
`#11: Description
`
`JUBLIA contains 100 mg of efinaconazole. Efinaconazole is an azole antifungal with a
`chemical name of ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-
`1,2,4-triazol-1-yl) butan-2-ol). The structural formula for efinaconazole is represented
`below:
`
`Molecular Formula: C18H22F2N4O Molecular Weight: 348.39
`JUBLIA contains the following inactive ingredients: alcohol, anhydrous citric acid,
`butylated hydroxytoluene, C12-15 alkyl lactate, cyclomethicone, diisopropyl adipate,
`disodium edetate, and purified water.
`
`#16: How Supplied/Storage and Handling
`
`JUBLIA (efinaconazole) topical solution, 10% is a clear, colorless to pale yellow solution
`supplied in a white plastic bottle with an integrated flow-through brush applicator as
`follows:
` 4 mL (NDC 0187-5400-04)
` 8 mL (NDC 0187-5400-08) Storage and Handling Conditions:
`Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F)
`[see USP Controlled Room Temperature].
`
`Reference ID: 3514834
`
`Page 4 of 5
`
`

`

` Solution is flammable; keep away from heat or flame
` Protect from freezing
` Keep out of the reach of children
` Keep bottle tightly closed
` Store in upright position
`
`2.
`
`Immediate container labels
`
`The image of the label for 4 mL bottle is shown below:
`
`Labels for 8 mL bottle and physician sample have the same information,
`
`
`
`Carton labeling
`3.
`The image of the label for 4 mL bottle is shown below:
`
`Cartons for 8 mL bottle and physician sample have the same information,
`
`
`
`Reference ID: 3514834
`
`Page 5 of 5
`
`(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/
`----------------------------------------------------
`
`BOGDAN KURTYKA
`05/29/2014
`
`MOO JHONG RHEE
`05/29/2014
`Chief, Branch IV
`
`Reference ID: 3514834
`
`

`

`
`
`NDA 203567
`
`Jublia (efinaconazole) topical solution
`10%
`
`Dow Pharmaceutical Sciences
`
`Bogdan Kurtyka, Ph.D.
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division New Drug Quality Assessment II, Branch IV
`
`For the Division of Dermatological and Dental Products (HFD—540)
`
`CMC REVIEW OF NDA 203567
`
`Reference ID: 3504123
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`CMC Review Data Sheet .........................................................................................3
`
`The Executive Summary .........................................................................................6
`
`I. Recommendations ....................................................................................................................... 6
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 6
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable N/A .......................................................................................... 6
`
`II. Summary of CMC Assessments .................................................................................................6
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 6
`
`B. Description of How the Drug Product is Intended to be Used.......................................................... 7
`
`C. Basis for Not-Approval Recommendation....................................................................................... 7
`
`III. Administrative........................................................................................................................... 7
`
`CMC Assessment......................................................................................................9
`
`I. Review of Response to Deficiencies ...........................................................................................9
`
`A. Deficiency l ..................................................................................................................................... 9
`
`B. Deficiency 2 ................................................................................................................................. 16
`
`C. Deficiency 3. .................................................................................................................................. 17
`
`D. Defic1ency423
`
`II. Review of New Information Submitted ...................................................................................24
`
`111. List of Deficiencies ............................................................................................................................. 32.
`
`CMC Review #2
`
`Page 2 of 33
`
`Reference ID: 3504123
`
`

`

`
`
`CMC Review Data Sheet
`
`CMC Review Data Sheet
`
`1. NDA 203567
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: 8-May-2014
`
`4. REVIEWER: Bogdan Kurtyka, Ph.D.
`
`5. PREVIOUS DOCUMENTS: CMC Review #1 with 3 addenda
`
`6. SUBMISSION(S) BEING REVIEWED:
`Submission; s) Reviewed
`Resubmission
`
`Labeling amendment
`
`Document Date
`20-Dec—2013
`
`16—Jan-2014
`
`7. NAME & ADDRESS OF SPONSOR:
`
`Name:
`
`Address:
`
`Telephone:
`Fax:
`
`Dow Phamiaceutical Sciences
`
`Pentaluma. CA 94954, USA
`
`707-796-7222
`707-793-0145
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`Jublia
`a) Proprietary Name:
`Efinaconazole
`b) Non-Proprietary Name (USAN):
`IDP-108
`c) Code Name/# (ONDQA only):
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type:
`
`0 Submission Priority:
`
`1
`
`S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY: Azole antifungal agent
`
`11. DOSAGE FORM:
`
`Solution
`
`CODE: 138
`
`12. STRENGTH/POTENCY:
`
`10%
`
`13. ROUTE OF ADMINISTRATION: Topical
`
`CODE: 011
`
`CMC Review #2
`
`Page 3 of 33
`
`Reference ID: 3504123
`
`

`

`
`
`CMC Review Data Sheet
`
`OTC
`‘1 Rx
`14. Rx/OTC DISPENSED:
`15. SPOTS (SPECIAL PRODUCTS ON-LINETRACKING SYSTEM):
`SPOTS product — Form Completed
`‘1 Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name:
`USAN Name:
`
`(2R,3R)—2-(2,4—difluorophenyl)—3-(4—methylenepiperidin— 1 -
`Eficonazole
`
`CAS Number:
`
`164650-44—6
`
`Structural Formula:
`
`CH2
`
`Molecular Formula: C 13H22F2N4O
`
`Molecular Weight:
`
`348.39
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`.4
`
`HOLDER
`
`ITEM
`REFERENCED CODEl STATUS2
`
`DATE
`REVIEW
`
`COMNIENTS
`
`COMPLETED Efinaconazole
`
`0’) (4
`
`Adequate
`
`13-Jan-2014. checked Reviewed by
`into DARRTS on 14- Dr. Bogdan
`Jan-2014
`K
`ka
`--_-
`
`Action codes for DMF Table:
`l — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed. as follows:
`2 —Type 1 DW
`3 — Reviewed previously and no revision since last review
`4 — Suflicient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`2 Adequate, Inadequate. or N/A (There is enough data in the application. therefore the DMF did not need to
`
`CMC Review #2
`
`Page 4 of 33
`
`Reference ID: 35041 23
`
`

`

`
`
`CMC Review Data Sheet
`
`be reviewed)
`
`B. Other Documents: N/A
`
`18. STATUS:
`
`RECOMIVIENDATION
`
`DATE
`
`REVIEWER
`
`
`ONDQA:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`N/A
`Biometn'cs
`————
`EES
`Pendin -
`—-———
`N/A
`Phann/Tox ———
`N/A
`Bio . harm
`-————
`LNC
`N/A
`————
`N/A
`Methods Validation
`————
`DMEPA
`N/A
`————
`['11>
`Categorical exclusion
`22-Jan-2013
`u anted (see Review #1)
`‘
`I uroval
`_'__—-5'-
`Microbi010313-Jan-2014 B an S. Rile . Ph.D.
`
`Bogdan Kmtyka. Ph.D.
`
`CMC Review #2
`
`Page 5 of 33
`
`Reference ID: 3504123
`
`

`

`
`
`Executive Summary Section
`
`The CMC Review for NDA 203567
`
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The applicant of this NDA has resubmitted to address the deficiencies listed in the
`Complete Response letter dated May 13, 2013, and now deemed to have provided
`sufficient information to assure the identity, strength, pruity, and quality of the drug
`product.
`
`The office of Compliance has not issued yet an overall “Acceptable” recommendation
`for this resubmission .
`
`Issues on the new label/labeling are not resolved as of the date of this review.
`
`Therefore, from the ONDQA perspective, this NDA is not ready for approval per
`21CFR 314.125(b)(6),(13) in its present form rmtil the above issues delineated in the
`“List of Deficiencies” (p. 32) are satisfactorily resolved.
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`N/A
`
`11. Summary of CMC Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`(1) Drug Substance
`The sponsor references DMF 21870 (Kaken Pharmaceuticals) for details on the
`description, characterization, manufacture, packaging, specification for quality control
`testing, and stability of the proposed drug substance,
`mm A
`letter of authorization to cross reference the DMF is provided in the application. The
`DMF 21870 has been reviewed and found adequate to support this application.
`
`(2) Drug Product
`Efinaconazole solution 10% is indicated for treatment of onychomycosis. It is a clear,
`colorless to pale yellow solution. The inactive ingredients of the formulation are
`commonly used in topical drug products. All except one (C 12-15 alkyl lactate)
`excipients are listed in the Inactive Ingredients Database and the proposed amounts do
`not exceed previously approved levels. The drug product is manufactured by (m4)
`
`CMC Review #2
`
`Page 6 of 33
`
`Reference ID: 3504123
`
`

`

`
`
`Executive Summary Section
`
`manufacturing site.
`
`mar The sponsor proposed Kaken Pharmaceutical (Japan) as the
`
`The drug product specification includes: appearance, package integrity, identification,
`assay of drug substance, impurities, assays of
`(m4)
`and microbial testing. The specification attributes and their analytical methods are
`deemed satisfactory for assuring the identity, strength, purity, and quality.
`
`Efinaconazole solution is packaged in a 10 mL HDPE bottle with a brush applicator in
`a
`m“) cap. The information included in the application demonstrates that the
`proposed container/closure system meets all recommendations of relevant USP
`monographs and the Agency’s guidance. The new container closure system and control
`of filling operation satisfactorily addresses all deficiencies listed in the Action Letter.
`
`The sponsor provided the results of 24 months long-term stability studies, and proposed
`an 36—month expiration dating period under the controlled room conditions. The
`proposed expiration dating period is supported by the submitted data.
`
`The applicant claimed categorical exclusion from the Environmental Assessment based
`on 21CFR 25.31(b).
`
`B. Description of How the Drug Product is Intended to be Used
`
`The drug product should be applied once daily using the built-in flow-through brush
`applicator. During application the nail, the nail folds, nail bed, hyponychium, and the
`undersurface of the nail plate, should be completely covered by the formulation.
`
`C. Basis for Not-Approval Recommendation
`
`21CFR 314.125(b)(6)
`0 Various sections of Package Insert including Highlights, Sections 3, 11 and 16 are
`inadequate.
`
`o The carton/container labels are inadequate.
`
`21CFR 314.125(b)(l3)
`
`o The Office of Compliance did not issue an overall “Acceptable” recommendation
`for the manufacturing establishments.
`
`(see the “List of Deficiencies” on p.32).
`
`III. Administrative
`
`CMC Review #2
`
`Page 7 of 33
`
`Reference ID: 35041 23
`
`

`

`
`
`Executive Summary Section
`
`A. Reviewer’s Signature:
`
`(See appended electronic signature page)
`Bogdan Kmtyka, PhD.
`CMC Reviewer, Branch IV/Division II/ONDQA
`
`B. Endorsement Block:
`
`(See appended electronic signature page)
`
`Moo-Jhong Rhee, PhD.
`Branch Chief, Branch IV/Division II/ONDQA
`
`C. CC Block:
`
`Entered electronically in DARRTS
`
`25 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`CMC Review #2
`
`Page 8 of 33
`
`Reference ID: 35041 23
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHULIN DING
`05/09/2014
`
`MOO JHONG RHEE
`05/09/2014
`Chief, Branch IV
`
`Reference ID: 3504123
`
`

`

`Initial Quality Assessment For Resubmission
`Branch IV
`
`Division of New Drug Quality Assessment 11
`
`0ND Division: Division of Dermatology and Dental Products
`NDA: 203-567
`
`Category Class 2 Resubmission
`Applicant: Dow Pharmaceutical Sciences.
`Stamp Date: Dec. 20, 2013
`PDUFA Date June 20, 2014
`Trademark:
`Jublia®
`Established Name: Efmaconazole
`
`Dosage Form: Solution
`Route of Administration: Topical
`Indication: Onychomycosis
`
`CMC Lead: Shulin Ding
`
`YES NO
`
`ONDQA Resubmission Completeness: XI
`
`|:|
`
`Summary and Critical Issues:
`
`A. Summary
`This review is the Initial Quality Assessment for the resubmission ofNDA 203567 Jublia®
`(efinaconazole) topical Solution, 10%. NDA 203567 is a Type 1 505(b)(1) NDA originally
`submitted to the FDA on July 26. 2012. It received a Complete Response action on May 13.
`2013 due to CMC deficiencies related to excessive product leakage. The applicant states in the
`cover letter of the resubmission that to address the deficiencies outlined in the CR action letter the
`
`originally proposed flow-thru bmsh applicator has been replaced with another applicator which is
`not prone to leaks. The new flow-thm bmsh applicator is supplied by
`“‘4’. Its
`design
`
`(mo
`
`The applicant further states that the formulation. method of bulk manufacturing of finished
`product, as well as the specifications and analytical methods for the drug substance. excipients.
`and finished product remain the same as before in the original submission. Only the
`container/closure system packaging operation and the drug product manufacturer are new.
`Additionally, there is one new testing lab
`M“) added to this NDA as a testing facility for
`the drug substance.
`
`To support the proposed product packaged in the improved applicator. the applicant provided the
`following information in the resubmission:
`
`CMC Information Submitted in Resubmission
`
`CMC Information Provided
`
`Comments
`
`Two fill sizes. 4 mL fill in 10 mL bottle and
`
`Reference to Type HI DMF m“, for the
`W" with a LOA
`U . ted Section P. 3 Manufacturin-
`for the
`
`New DMF. No review has been conducted.
`
`Reference ID: 3434505
`
`

`

`
`
`following :
`
`(a)
`
`(b) (4)
`
`8 mL fill in 10 mL bottle. are proposed.
`The 4 mL fill in 10 mL bottle is also the
`
`physician sample size.
`
`(b) New fill sizes are proposed.
`(c) A new DP manufacturer (Kaken
`Pharmaceutical) is proposed. replacing the
`originally proposed
`M“) .
`(d) A new commercial scale batch size.
`to 0 - sed.
`
`mm is
`
`Updated Section P. 2.4 and R7 Container/Closure
`for the proposed applicator. The following
`information is provided:
`(a) Description
`(b) Specifications
`(c) Results of extractables studies per
`USP<661> and USP<671>
`
`(d) Comparison between the improved
`applicator and the original one including
`drop size and dosing amount in a
`
`The comparison tables are reproduced and
`presented on the following page.
`
`drug. ethanol. and related substances.
`
`I-
`5
`
`U - ted SectionP.5 Dru- Products '
`
`Batch analysis for 6 Kaken M“) batches packaged
`in the improved applicator (
`(b) (4)
`
`Batch size:
`
`Proposed expiration dating period is 36 month
`at USP controlled room temperature
`
`Package integrity and weight loss were
`included in the protocol in addition to assay of
`
`24 months of registration stability data from three
`Kake- (bm) batches packaged in the improved
`applicator (accelerated. and long term) for each fill
`size. Both upright and horizontal orientations
`were investi - ated.
`
`In-use stability studies
`1.5 months. 10 units of 8 mL size. A total of g}
`applications
`(”‘4’ were
`dispensed through the bmsh. Each drop weight
`was measured.
`
`Photostability and freeze/thaw cycling studies
`
`I-
`
`H
`
`Post approval stability commitment
`Label/labeling
`Executed packaging records and Master Batch
`Record
`
`Reference ID: 3434505
`
`

`

`Comparison of To-Be-Marketed Container with the Original Container
`
`To-be—marketed Container
`Closure
`
`Formulation (Qualitative and Quantitative)
`Efmaconazole
`lO°-'
`
`_xcipientsSam—
`Packae
`
`Original XDA Container
`Closure
`
`1b) (4)
`
`It.
`
`
`10 1111. capacity
`Flow Tliru Design with Bmsh
`Applicator
`Inside Plug —
`Blush -
`
`m“)
`
`Cap—
`
`Apply product to the nail and use
`brush to spread solution
`
`M“)
`US FDA Registered FacilitVr
`
`Blush Cap
`
`Fill Size
`
`dro
`
`Manufacturing
`Location
`
`Dose Comparison of To—Be—Marketed Container with the Original Container
`
`Daily Dose (pL)
`Aierage i SD
`(minimum-maximum)
`
`Cumulative use for 28 days (pl)
`Average t SD
`(minimum-maximum)
`
`(minimum-maximum)
`
`Percent use against P3 container
`Average
`
`Reference ID: 3434505
`
`

`

`Formulation Composition for the Proposed To—Be—Marketed Formulation
`(no change in formulation composition)
`
`Ingredient
`
`Grade
`
`Total
`\Velght In
`8—mL Fill
`
`Size (g)
`
`Size (g)
`
`u» m
`
`
`
`
`
`Total
`Function
`Concentration
`
`(Wow/w)
`Welght lll
`
`
`
`4—mL Fill
`
`
`
`00(4)
`
`
`Et'maconazole
`.
`Cyclomethicone
`
`Diisopropyl Adipate
`
`C 1 2-1 5 Alkyl Lactate
`
`Cosmetic
`
`Cosmetic
`
`Butylated
`Hydroxytoluene
`Citric Acid. Anhydrous
`Edetate Disodium
`
`Purified “Utter
`
`
`
`Alcohol
`
`
`
`
`
`B. Critical issues for review
`
`1. Reviewer should look into the adequacy of in-process controls and drug product
`specification to support this product especially regarding leakage issue.
`
`2. Reviewer should assess whether the manufacturing process (especially the
`o’w/plugging/capping operation) used by the registration stability batches is
`representative of the commercial process (i.e. compare executed batch records with
`Master Batch Record).
`
`C. Consults:
`
`CONSULT
`
`COMB/IENTS
`
`Establishment Evaluation
`Reuest ER
`
`Submitted on Jan. 6. 2014
`
`Pharmacolos ffoxicolos -n—
`NME. Method validation request was sent in the first
`cycle review. and the review was filed in DARRTS on
`Feb. 22. 2013.
`
`Methods Validation
`
`—_nc cle revrew.
`
`
`
`Product quality microbiology reviewer assignment was
`requested but not made. Email received from CDER
`OPS IO MICRO indicated that the submission is
`
`acceptable from a product microbiology standpoint. and
`will be recommended for approval. A review memo
`describing the assessment of the microbial controls for
`the dm- roduct will be entered into DARRTS.
`
`Reference ID: 3434505
`
`

`

`D. Comments/Recommendation:
`
`The submission has addressed the deficiencies outlined in the CR action letter dated May
`13, 2013 in completeness. Therefore, a substantial review can be performed from the
`CMC perspective.
`
`Both drug substance and drug product manufacturing sites are located in Japan. GMP
`inspection requests have been submitted.
`
`The assigned CMC reviewer to this NDA is Dr. Bogdan Kurtyka. Biopharm review is
`not needed since this is a solution product. Product quality microbiology review was
`performed by Vera Viehmann.
`
`{See appended electronic signature page}
`Shulin Ding, Ph.D.
`CMC Lead
`Division of New Drug Quality Assessment II
`Office of New Drug Quality Assessment
`
`{See appended electronic signature page}
`Moo-Jhong Rhee, Ph.D.
`Branch Chief
`Division of New Drug Quality Assessment II
`Office of New Drug Quality Assessment
`
`Date
`
`Date
`
`Reference ID: 3434505
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHULIN DING
`01/10/2014
`
`MOO JHONG RHEE
`01/10/2014
`Chief, Branch IV
`
`Reference ID: 3434505
`
`

`

`
`
`
`
`
`
`Memorandum
`
`
`Date:
`To:
`
`
`From:
`
`
`Through:
`
`
`CC:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`10-May-2013
`CMC Review #1 for NDA 203567
`
`Bogdan Kurtyka, Ph.D.
`CMC Reviewer, ONDQA Division II
`
`Moo-Jhong Rhee, Ph.D.
`Chief, Branch IV ONDQA Division II
`
`Shulin Ding, Ph.D.
`CMC Lead, ONDQA Division II
`
`Update on Facility Inspection
`
`
`Subject:
`
`CMC Review #1 dated 07-Feb-2013 and Addenda dated 1-Mar-2013 and 11-Apr-2013 noted
`multiple deficiencies which mostly originated from a leakage problem in the container/closure
`system, and two other unresolved issues (inadequate information regarding manufacturing
`process and process controls, and labeling). In addition, cGMP compliance evaluation of the
`facilities involved in this application was not yet completed.
`
`On 09-May-2013 the Office of Compliance issued an overall “Acceptable” recommendation for
`facilities listed in the application (see the Appendix). Nevertheless, the NDA continues to be
`inadequate for approval because the aforementioned CMC and labeling deficiencies remain
`unresolved.
`
`The information needed to resolve the deficiencies remains the same as in the Addendum dated
`11-Apr-2013, with the exception of Item #5 on GMP compliance, which has been resolved.
`
`
`
`
`
`
`
`Reference ID: 3307164
`
`Page 1 of 3
`
`

`

`
`
`
`
`
`
`Appendix:
`
`
`
`
`
`
`
`Reference ID: 3307164
`
`Page 2 of 3
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`
`
`DRUG SUBSTANCE STABIUTY TESTER
`FINISHED DOSAGE MANUFACTURER
`
`FINISHED DOSAGE STABIUTY TESTER
`
`WLIOUID (OTHER THAN SUSP &
`0C RECOWBIDATION
`
`OAI Sm:
`
`NONE
`
`I 1-OCT—2012
`
`ACCEPTABLE
`
`DISTRICT RECMNDATICN
`
`Emmi-mm:
`
`DIF No:
`
`Responsbllnles:
`
`Pl’oflle:
`Last “Cum:
`
`Milestone Um:
`
`Decision:
`
`Reason:
`
`
`
`ResponsuIItIes:
`Profile:
`
`L... ”Mm;
`
`Iilestone Data:
`
`Decision:
`
`nelson:
`
`FINISHED DOSAGE RELEASE TESTER
`CONTROL TESTING LABORATORY
`
`OAI Sm:
`
`NONE
`
`OC RECOWENDATION
`
`06-AUG-2012
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`
`
`Responsibilities:
`
`Profile:
`Last Milestone:
`
`Ililalone Date:
`
`DecIsIon:
`
`Reason:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE STABILITY TESTER
`
`—m av CHEMICAL SYNTHESIS
`0C RECOWENDATION
`
`OAI status:
`
`NONE
`
`cum-2013
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Reference ID: 33071 64
`
`Page 3 of 3
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BOGDAN KURTYKA
`05/10/2013
`
`MARIE KOWBLANSKY on behalf of MOO JHONG RHEE
`05/10/2013
`
`Reference ID: 3307164
`
`

`

`MEMORANDUM
`
`Date: April 12, 2013
`
`To: NDA 203-567
`
`From: Terrance Ocheltree, Ph.D., R.Ph.
`Director
`Division of New Drug Quality Assessment II
`ONDQA
`
`
`Subject: Tertiary review of ONDQA recommendation for NDA 203-567,
`
`(efinaconazole) Topical Solution, 10%. Efinaconazole is a new molecular entity (NME).
`
` I
`
` have assessed the ONDQA review of NDA 203-567 by Bogdan Kurtyka, Ph.D. The initial
`ONDQA CMC review was entered into DARRTS on February 8, 2013, with a recommendation
`for a Complete Response due to a lack of sufficient information to assure the identity, strength,
`purity, and quality of the drug product; an absence of a recommendation from the Office of
`Compliance on the manufacturing and testing sites; and pending labeling issues. The ONDQA
`review was amended in DARRTS on March 1, 2013 by Dr. Kurtyka to generate a Discipline
`Review (DR) Letter. The DR Letter was sent to the applicant on March 8, 2013. A
`teleconference was held with the applicant on March 12, 2013 and the applicant submitted an
`information amendment on March 19, 2013. A subsequent teleconference was held with the
`applicant on March 20, 2013 to provide further clarifications for the deficiencies outlined in the
`DR Letter. A second amendment to the ONDQA CMC review was entered into DARRTS on
`April 11, 2013, restating the deficiencies regarding the drug product, manufacturing process,
`labeling, and manufacturing and testing sites overall recommendation. The Overall
`Recommendation for site acceptability is still pending from the Office of Compliance.
`
`An ONDQA Biopharmaceutics review was not performed since the product is a topical solution.
`Therefore, bioavailability and biopharmaceutics are not an issue.
`
` A
`
` Method Validation Consult Request was generated to evaluate the test methods for Assay and
`Impurities for drug substance and drug product. The Method Validation Report Summary was
`entered into DARRTS on February 22, 2013, stating the methods are acceptable for quality
`control and regulatory purposes.
`
`
` contains efinaconazole manufactured and tested by Kaken Pharmaceutical Co., Ltd. The
`drug substance is referenced by appropriate Letter of Authorization (LOA) to a Drug Master File
`(DMF), DMF 21870. The DMF was reviewed and found to be adequate to support this NDA.
`The review was entered into DARRTS on December 12, 2012.
`
`
` is packaged in a 10 mL HDPE bottle with a brush applicator
`
`
`
`Reference ID: 3292772
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`I concur with the determination that the information as provided in the NDA is not adequate to
`assure the identity, strength, purity, and quality of the drug product, and the overall Quality
`recommendation of Complete Response.
`
`Secondary review of the CMC reviews was performed by Moo-Jhong Rhee, Ph.D.
`
`Reference ID: 3292772
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TERRANCE W OCHELTREE
`04/12/2013
`
`Reference ID: 3292772
`
`

`

`
`
`
`
`
`
`Memorandum
`
`
`
`
`
`
`
`
`
`
`
`Date:
`To:
`
`
`From:
`
`
`Through:
`
`
`CC:
`
`
`
`
`Subject:
`
`
`
`
`
`
`
`
`
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`
`11-Apr-2013
` CMC Review #1 for NDA 203567
`
`
`
`
`
`
`
`Bogdan Kurtyka, Ph.D.
`CMC Reviewer, ONDQA Division II
`
`Moo-Jhong Rhee, Ph.D.
`Chief, Branch IV ONDQA Division II
`
`Shulin Ding, Ph.D.
`CMC Lead, ONDQA Division II
`
`Final CMC Recommendation and the Proposed
`Complete Response letter
`
`
`CMC Review #1 dated 07-Feb-2013 and Addendum dated 1-Mar-2013 noted multiple
`deficiencies which mostly originated from the leakage problem of the container/closure system,
`and two other unresolved issues. Because of these deficiencies, in the last Addendum, “Non
`Approval” action was recommended.
`
`After the 1-Mar-2013 Addendum was signed off and filed, a CMC discipline review letter was
`sent to the sponsor on 8-Mar-2013, and a teleconference was held on 12-Mar-2013 to inform the
`applicant of CMC review conclusion. Subsequently, the sponsor submitted an information
`amendment on 19-Mar-2013, and a teleconference with the sponsor was held on 20-Mar-2013 to
`provide further clarifications for the deficiencies outlined in the discipline review letter.
`
`The purpose of this addendum is to affirm the previous CMC recommendation of “Non
`Approval” and, due to the complexity of the issues, to further elaborate the deficiencies
`delineated in the 1-Mar-2013 addendum in order to communicate more clearly to the applicant
`via a CR action letter.
`
`The following is the revised language recommended for the CR action letter:
`
`DEFICIENCIES
`
`The quality of the product can not be assured due to:
`
`
`1. Inadequate manufacturing process and control information of the
`filling/capping
` operation
`
`
`
`Reference ID: 3291952
`
`Page 1 of 7
`
`(b) (4)
`
`

`

`
`
`
`
`Per 21 CFR 314.50 (d)(1)(ii)(c), the application shall contain the proposed or actual
`master production record, including a description of the equipment, to be used for the
`manufacture of a commercial lot of the drug product or a comparably detailed description
`of the production process for a representative batch of the drug product. The description
`is expected to be included in Section 3.2.P.3 of the application.
`
` process in the
`However, the application did not describe the filling/capping
`Section P.3 as well as in the Master Batch Record with sufficient details and specifics to
`ensure the process is robust and can produce batches with acceptable leakage rate.
`
`Report 129 in the Developmental Section concluded with recommendations on processes
`improvement, stating that additional enhancements are necessary as follows:
`
`
`•
`•
`•
`
`
`But none of the recommendations of the Report 129 on the process improvement are
`officially implemented in the Section P3 (manufacturing process) and in Master Batch
`Record. (Note that Report 129, included in Section 3.2.P.2, is not considered a binding
`agreement with the Agency.)
`
`2. Inadequate specification for the drug product
`
`Stability study results on weight loss for the mL fill stored at 25ºC confirms a
`significant loss of formulation i