`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`204592Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`ESTABLISHMENT EVALUATION REQUEST
`
`Ilicatlon:
`
`mp Date:
`
`mi
`
`,1:
`
`illcant:
`
`NDA 204592/000
`
`20-DEC-2012
`
`20-OCT-2013
`
`IROKO PHARMS LLC
`1 KEW PL 150 ROUSE BLVD
`
`PHILADELPHIA, PA 19112
`
`why:
`
`£0“:
`
`3
`
`170
`
`illcatlon Comment:
`
`DETAIL REPORT
`
`Action Goal:
`
`District Goal:
`
`21 -AUG-2013
`
`ZORVOLEX (DICLOFENAC ACID)
`
`Brand Name:
`Estab. Name:
`
`Generic Name:
`
`Product Number; Dosage Form; Ingredient; Strengths
`
`001; CAPSULE; DICLOFENAC; 18MG
`002; CAPSULE; DICLOFENAC; 35MG
`
`\ Contacts:
`
`Y. WANG
`
`Prod Qual Reviewer
`
`S. DONALD
`
`L. RIVERA
`
`Micro Reviewer
`
`Product Quality PM
`
`(HFD-805)
`
`8. PATWARDHAN
`
`Regulatory Project Mgr
`
`(HF-01)
`
`3017961479
`
`3017960586
`
`3017964013
`
`3017964085
`
`J. PINTO
`Team Leader
`3017961733
`
`
`ran Recommendation:
`
`ACCEPTABLE
`
`on
`
`"M" by C. CAPACCI-DANIEL
`
`()
`
`3017963532
`
`by EES_PROD
`on 31 -JAN-2013
`PENDING
`
`
`Ictobor 15, 201310:12 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 1 of 5
`
`

`

`abllshment:
`
`CFN:
`
`(II) (4)
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`FEI:
`
`(b) (4)
`
`(b) (4)
`
`F No:
`
`AADA:
`
`.ponoibilitles:
`
`DRUG SUBSTANCE RELEASE TESTER
`
`FINISHED DOSAGE MANUFACTURER
`
`11"“th
`"went:
`lilo:
`
`TEST RAW MATERIALS, MANUFACTURE DRUG PRODUCT, TEST
`DRUG PRODUCT. STORE AND PERFORM. STABILITY TESTING. (on
`CAPSULES, PROMPT RELEASE
`
`MmMATERIALS, RELEASE TESTING OF
`“Why L. RIVERA () 3017964013)
`OAI Status:
`NONE
`
`:etone Name
`Comment
`sMITTED To CC
`
`IMITTED To Do
`CHG INITIAL
`
`Milestone Date
`
`Rgues’t T123
`
`31 -JAN-201 3
`
`Planned Completion Decision
`__ Reason
`
`31-JAN-2013
`
`10-Day Letter
`
`Creator
`
`RIVERAL
`
`SHARPT
`
`m"
`RECOMMENDATION
`AN ABBREVIATED CGMP/PAI FOR THE SAME PROFILE CLASS (CHG) WAS CONDUCTED
`(W) No FDA 483 WAS ISSUED. BASED ON FILE REVIEW, KAN-DO RECOMMENDS
`APPROVABLE.
`
`SBERRYMA
`@AgCEPTABLE
`BASED ON FILE REVIEW
`
`RECOMMENDATION
`
`"M"
`
`SHARPT
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`Ictober 15, 2013 10:12 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 2 of 5
`
`

`

`mush-mm:
`
`CFN:
`
`W"
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`FEI:
`(mo
`
`“9‘"
`
`: No:
`
`AADA:
`
`.ponsIbImIes:
`
`FINISHED DOSAGE PACKAGER
`
`abllohm
`W:
`illo:
`
`PACKAGING AND LABELING OF DRUG PRODUCT, CONTROL OF PACKAGING CONTAINER CLOSURE COMPONENT (on
`(Why L. RIVERA 0 3017964013)
`CAPSULES, PROMPT RELEASE
`
`OAI Status:
`
`NONE
`
`m ugmo
`Milestone Date
`Rgguest Tme
`Planned Completign Decision
`Creator
`
`Comment
`Reason
`IMITTED TO 00
`31-JAN-2013
`RIVERAL
`
`RECOMMENDATION
`
`0”“)
`
`ACCEPTABLE
`BASED ON PROFILE
`
`SHARPT
`
`Ictobor 15, 2013 10:12 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 3 of 5
`
`

`

`ablishrnent:
`
`CFN:
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`FEI:
`
`W"
`
`(m4)
`
`F No:
`
`AADA:
`
`ponslbllltlos:
`
`DRUG SUBSTANCE RELEASE TESTER
`
`Ibllsh'ment
`nmen :
`me:
`
`DRUG SUBSTANCE LABORATORY TESTING (on
`CONTROL TESTING LABORATORY
`
`(W) by L. RIVERA () 3017964013)
`OAI Status:
`NONE
`
`Planned Completion Decision
`Rguut TIE
`Milestone Date
`gone Name
`km Reason
`IMITTED TO 00
`31—JAN-2013
`
`Creator
`
`RIVERAL
`
`RECOMMENDATION
`
`(m4)
`
`ACCEPTABLE
`
`SHARPT
`
`BASED ON PROFILE
`
`Ictoher 15, 2013 10:12 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 4 of 5
`
`

`

`abllshment:
`
`CFN:
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`(5) (4)
`
`FEI:
`
`(6)“)
`
`F No:
`
`AADA:
`
`ponsibllitlos:
`
`DRUG SUBSTANCE MANUFACTURER
`
`DRUG SUBSTANCE STABILITY TESTER
`
`ibl'ahtmm
`amen :
`llle:
`
`DRUG SUBSTANCE MANUFACTURER & STABILITY TESTING (on
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`(”may L. RIVERA 0 3017964013)
`OAI Status:
`NONE
`
`Istono Name
`Milestone Date
`Reguest Txge
`Planned Completion Decision
`
`Comment
`SMITTED To 00
`31 -JAN-2o13
`
`Reason
`
`3Ml1TED To DO
`LAST INSPECTION FOR CSN
`
`GMP Inspection
`31 -JAN-2013
`(W) GREATER THAN 3 YRS
`
`SIGNED INSPECTION T0 IB
`
`09-FEB-2013
`
`GMP Inspection
`
`RECOMMENDATION
`
`(b) (4)
`
`ACCEPTABLE
`
`Creator
`
`RIVERAL
`
`SHARPT
`
`PHILPYE
`
`PH ILPYE
`
`RECOMMENDATION
`
`M"
`
`BASED ON FILE REVIEW
`
`CAPACCIDANIC
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`Ictober 15, 2013 10:12 AM
`
`FDA Confidential - lntemal Distribution Only
`
`Page 5 of 5
`
`

`

`HM“
`
`FM“
`
`NDA 204592
`
`Zorvolex (Diclofenac) Capsules
`
`Iroko Pharmaceuticals, LLC
`
`Ying Wang, PhD
`
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment III
`Branch VIII
`
`For the Division of Anesthesia, Analgesia and Addition Products
`
`CMC REVIEW OF NDA 204592
`
`Reference ID: 3374444
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`CMC Review Data Sheet .........................................................................................4
`
`The Executive Summary .........................................................................................9
`
`I. Recommendations ....................................................................................................................... 9
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 9
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements, and/or Risk
`Management Steps. if Approvable ................................................................................................... 9
`
`II. Summary of CMC Assessments .................................................................................................9
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 9
`
`B. Description of How the Drug Product is Intended to be Used....................................................... 10
`
`C. Basis for Approvability or Not-Approval Recommendation ......................................................... 10
`
`III. Administrative......................................................................................................................... 11
`
`CMC Assessment.................................................................................................... 12
`
`I. Review Of Common Technical Document-Quality (Ctd—Q) Module 3.2: Body Of Data ....... 12
`
`S DRUG SUBSTANCE .................................................................................................................... 12
`8.1
`General Information ........................................................................................................................ 12
`8.2
`Manufacture .................................................................................................................................... 14
`8.3
`Characterization .............................................................................................................................. 15
`
`8.4
`8.5
`
`8.6
`s.7
`
`Control of Drug Substance .............................................................................................................. 17
`Reference Standards or Materials ................................................................................................... 28
`
`Container Closure System ............................................................................................................... 29
`Stability ........................................................................................................................................... 29
`
`P DRUG PRODUCT ........................................................................................................................ 30
`
`R]
`P2
`P3
`
`PA
`P5
`P.6
`
`R7
`RS
`
`Description and Composition of the Drug Product ......................................................................... 30
`Pharmaceutical Development.......................................................................................................... 32
`Manufacture .................................................................................................................................... 34
`
`Control of Excipients ...................................................................................................................... 39
`Control of Drug Product ................................................................................................................. 40
`Reference Standards or Materials ................................................................................................... 61
`
`Container Closure System ............................................................................................................... 64
`Stability ........................................................................................................................................... 65
`
`A APPENDICES .............................................................................................................................. 70
`
`Al
`A2
`A3
`
`Facilities and Equipment (biotech only) ......................................................................................... 70
`Adventitious Agents Safety Evaluation .......................................................................................... 70
`Novel Excipients ............................................................................................................................. 70
`
`R REGIONAL INFORMATION ..................................................................................................... 70
`
`CMC Review #1
`
`Page 2 of 71
`
`Reference ID: 3374444
`
`

`

`F'AEH
` FFAEH
`,
`t
`CMC REVIEW OF NDA 204592 w
`
`R1
`
`Executed Batch Records ...................................................................................................................... 70
`
`R2 Comparability Protocols ...................................................................................................................... 70
`R3 Methods Validation Package ............................................................................................................... 70
`
`II. Review Of Common Technical Document-Quality (Ctd—Q) Module 1 .................................. 71
`
`A. Labeling & Package Insert ............................................................................................................. 71
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion .................................................. 71
`
`III. List Of Deficiencies to be Communicated ............................................................................... 71
`
`CMC Review #1
`
`Page 3 of 71
`
`Reference ID: 3374444
`
`

`

`
`
`CMC Review Data Sheet
`
`CMC Review Data Sheet
`
`1. NDA 204592
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: Sept. 16, 2013
`
`4. REVIEWER: Ying Wang, PhD
`
`5. PREVIOUS DOCUMENTS: N/A
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 5) Reviewed
`Original Submission
`Correspondence (C)
`Amendment (BC)
`Amendment (BC)
`
`Document Date
`
`12/20/2012
`5/1/2013
`8/15/2013
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Iroko Pharmaceuticals, LLC
`Address: 150 Rouse Blvd., Philadelphia, PA 19112
`Representative: Michelle Wilson, 100 Springhouse Dr. Suite 205,
`Collegeville, PA 19426
`Telephone: 513-829-1 108
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Zorvolex Capsules
`b) Non-Proprietary Name: Diclofenac
`c) Code Name/# (ONDQA only):
`d) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 5
`
`0 Submission Priority: Standard
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(2)
`
`10. PHARMACOL. CATEGORY: NSAID
`
`ll. DOSAGE FORM: Capsule
`
`CMC Review #1
`
`Page 4 of 71
`
`Reference ID: 3374444
`
`

`

`
`
`CMC Review Data Sheet
`
`12. STRENGTH/POTENCY: 18 mg, 35 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`l4. Rx/OTC DISPENSED:
`
`‘1 Rx
`
`OTC
`
`15- SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM ):
`SPOTS product — Form Completed
`
`j
`
`Not a SPOTS product
`
`1. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical name(s)(IUPAC)
`
`2-[2-(2.6-dichlorophenylamino)phcnyl]acetic acid
`
`Other chemical name(s)
`
`[o—(Z.6—dichloroanilino) phenyl] acetic acid
`
`1- 307 86 -
`
`Other non—proprietary name(s)
`
`Diclofcnac acid
`
`USAN:INN‘
`
`Diclofcnac
`
`Chemical Abstracts Service
`(CAS) registry number
`
`5
`
`- 5
`
`C |
`
`N H
`
`Cl
`
`OH
`
`0
`
`Molecular Formula
`
`CMC Review #1
`
`Page 5 of 71
`
`Reference ID: 3374444
`
`

`

`I'm".
`
`CMC REVIEW OF NDA 204592
`CMC Review Data Sheet
`
`"'"*"'E
`
`CanClzNOz
`
`Molecular Weight: 296.15
`
`CMC Review #1
`
`Page 6 of 71
`
`Reference ID: 3374444
`
`

`

`‘ -i-n
`
`1‘m- l\
`
` CMC REVIEW OF NDA 204592
`CMC Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`HOLDER
`
`DATE
`REVIEW COMMENTS
`COMPLETED
`
`mll- m«I.-
`
`
`
`II-
`II-
`II-
`II-
`II-
`II-
`III”?
`
`!————
`
`I
`I
`I
`
`I I I
`
`WI__II---
`
`1 Action codes for DMF Table:
`l — DMF Reviewed
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Suflicient information in application
`
`CMC Review#l
`
`Page7 of7l
`
`Reference ID: 3374444
`
`

`

`
`
`CMC Review Data Sheet
`
`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 be reviewed)
`
`B. Other Documents: N/A
`
`18. STATUS:
`
`ONDQA:
`CONSULTS/ CMC
`RELATED REVIEWS
`Biometrics
`
`RECONIMENDATION
`N/A
`
`DATE
`
`EES
`Pharm/Tox
`
`1 table
`Acc -
`A roval
`
`6/13/2013
`9/16/2013
`9/16/2013
`
`Ofiice of Com - liance
`Alex Xu
`Banu Zolnik
`
`————
`Methods Validation
`N/A, according to the
`current ONDQA olic
`
`
`
`DMEPA
`
`EA
`
`Microbiolo 3
`
`9/12/2013
`
`Vic Borders-Hen .mn
`
`Categorical exclusion (see
`NDA review)
`
`4/4/2013
`
`Steven P. Donald
`
`CMC Review #1
`
`Page 8 of 71
`
`Reference ID: 3374444
`
`

`

`
`
`Executive Summary Section
`
`The CMC Review for NDA 204592
`
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA is recommended for approval from Chemistry, Manufacturing, and Control
`(CMC) perspective. 24 months shelf life is proposed and granted when stored at 25°C
`(77°F) with excursions permitted to 15°C-30°C (59°F—86°F).
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`N/A
`
`II. Summary of CMC Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`(1) Drug Substance
`
`Drug substance diclofenac (also referred to as diclofenac acid) is white to off-white
`(m4) powder. It is freely soluble in dimethyl formamide and dimethyl sulfoxide
`and is practically insoluble in water. Drug substance information is referenced in DIVIF
`(no) for which
`M" is the holder. Specifications as
`amended are adequate and meet ICH Q3A guideline.
`
`(2) Drug Product
`
`Zorvolex capsules are provided in two strengths, 18 mg and 35 mg. Both strengths
`contain
`(I'm white to off-white powder encapsulated in hard gelatin
`capsule shells. The 18 mg capsules have a blue body imprinted with IP-203 and light
`green cap imprinted with 18 mg in white ink. The 35 mg capsules have a blue body
`imprinted with lP-204 and green cap imprinted with 35 in white ink.
`
`Pharmaceutical development information is referenced to the DMF 26224 for which the
`applicant Iroko Phann is the holder. The ZorvolexTM Capsules commercial
`manufacturing process involves
`
`(m4)
`
`CMC Review #1
`
`Page 9 of 71
`
`Reference ID: 3374444
`
`

`

`
`
`Executive Summary Section
`
`(5) (4)
`
`The drug products are packaged in high density polyethylene (HDPE) bottles. The
`submitted drug product stability data include 12 months at long term storage condition of
`25°C/60%RH and 6 month accelerated storage condition of 40°C/75%RH for 3 batches
`of each strength. The stability data supports the proposed 24 month shelf life for the drug
`product when stored at the proposed 25°C (77°F), excursions permitted between 15°C
`and 30°C (between 59°F and 86°F).
`
`B. Description of How the Drug Product is Intended to be Used
`
`The drug product is indicated for treatment of mild to moderate acute pain in adults. The
`recommended dose is 18 mg or 35 mg three times daily. Used the lowest effective dose
`for the shortest duration consistent with individual patient treatment goals.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`This is a 505 (b)(2) application with Cataflam (diclofenac potassium) as the reference
`drug. The drug substance specifications as amended are adequate and meet ICH Q3A
`guideline. The drug product Zorvolex Capsules are made
`M"
`. Both 10
`(m4) dose strength is achieved by fill weight.
`mg and 35 mg capsules
`The drug products are stable and there is no apparent trend during stability. The drug
`product specifications as amended are adequate and meet ICH Q3B guideline.
`
`An overall “Acceptable” recommendation was issued by the Office of Compliance on
`June 13, 2013.
`
`CMC Review #1
`
`Page 10 of 71
`
`Reference ID: 3374444
`
`

`

`
`
`Executive Summary Section
`
`III. Administrative
`
`A. Reviewer’s Signature:
`
`(See appended electronic signature page)
`
`Ying Wang, PhD
`
`B. Endorsement Block:
`
`(See appended electronic signaturepage)
`
`Prasad Peri, PhD, Branch Chief, Branch V111, ONDQA
`
`C. CC Block: entered electronically in DFS
`
`CMC Review #1
`
`Page 11 of 71
`
`Reference ID: 3374444
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`YING WANG
`09/16/2013
`
`PRASAD PERI
`09/17/2013
`I concur
`
`Reference ID: 3374444
`
`

`

`PRODUCT QUALITY — BIOPHARMACEUTICS
`
`FILING REVIEW
`
`NDA Number
`
`NDA 204592
`
`
`
`Clinical Division
`
`Division of Anesthesia. Anal {esia and Addiction Products
`
`Sandra Suarez—Sh . PhD
`
`Anelica Dorantes. PhD
`
`The following parameters for the ONDQA’s Product Quality-Biopharmaceutics filing checklist are
`necessary in order to initiate a full biopharmaceutics review (i.e.. complete enough to review but may
`have deficiencies).
`
`0NDQA—BIOPHARMACEUTICS
`A. INITIAL OVERVIEW OF THE NDA APPLICATION FOR FILING
`
`-
`
`Parameter
`
`-m Comment
`
`Does the application contain
`dissolution data?
`
`X
`
`USP I (basket). 100 rpmd’ 900 mL of 10 mM
`citric acid buffer (pH 5. )5) with 0.05 SLS
`(
`
`I. Q‘ WM“ 2° “W“
`
`_ (5)0
`
`.
`
`‘
`
`
`
`Is the dissolution test part of the DP
`
`secifications?
`
`Does the application contain the
`dissolution method development
`report?
`
`4.
`
`5.
`
`Is there a validation package for the
`analytical method and dissolution
`methodolo 3 ?
`Does the application contain in
`.
`.
`.
`v1tro alcohol induced dose dumpmg
`studies?
`
`Does the application include a
`biowaiver request?
`
`Report contains data on the solubility of
`diclofenac in difi'erent media pH. surfactant
`levels in the media. and basket rotational
`speed. Discriminating ability of the
`dissolution method was tested with several
`formulations intentionally manufactured to
`exhibit different dissolution .rofiles.
`
`X
`
`X
`
`X
`
`X
`
`.
`.
`.
`Alcohol induced dose dumping studies are not
`. d f
`111
`.
`di
`1
`f
`.
`require
`or nnme ate re ease orm anons.
`
`The applicant conducted PK studies with
`proof of concept formulation and commercial
`formulations with both strengths of 18 mg and
`35 m.
`
`'
`
`su» . 0 it the biowaiver re c uest?
`
`I__-
`u—ll—IVIVC model?
`
`File name: NDA 204592 Product Quality - Biopharmaceutics Filing Review.d0c
`
`Page 1
`
`Reference ID: 3267426
`
`

`

`PRODUCT QUALITY — BIOPHARMACEUTICS
`
`FILING REVIEW
`
`classification mentioned. and
`su. . .rtive data rovided?
`
`X
`
`..m”°"mg“‘° II—product with foods or liquids
`
`included?
`
`X
`
`
`
`Is there any in viva BA or BE
`information in the submission?
`
`Are there any manufacturing
`changes implemented to the clinical
`trial and bio batch formulations?
`
`Is there any data submitted to
`support the manufac
`. g changes
`flgfigfifigzfils?cal trial and
`'
`
`.
`
`313:3; :Egfigosgdudlitsfghtfiion
`5 ecification"
`P
`‘
`
`X
`
`X
`
`The applicant conducted the following two BE
`studies:
`
`Phase 1 DIC 1-08—01: Single dose five way
`cross over studies with proof of concept
`formulations of 18 mg (fast). 35 mg (fast and
`fed). and Cataflam 50 mg (fast and fed).
`Phase 1 DIC 1-12-07: Single dose five way
`cross over studies with commercial
`
`formulations of 18 mg (fast). 35 mg (fast and
`fed). and Cataflam 50 mg (fast and fed). These
`studies will be reviewed b OCP.
`
`Components of the Proof of Concept
`formulation and Commercial Formulation are
`different from each other. However. the
`dissolution specifications were set based on
`the commercial formulation.
`
`Bioavailability studies were conducted on
`both.formulations. See Comment 1‘1 above.
`Additionally. comparative dissolution data
`submitted from POC formulation and
`Commercial formulation for 35 m stren- h.
`
`Dissolution acceptance criterion was set based
`on the batches used in the clinical study. and
`
`biobatches. Refer to Dissolution Summary
`Tables below for more information on the
`batches used in the clinical studies as well as
`in the dissolution studies.
`
`B. FILING CONCLUSION
`
`__
`IS THE BIOPHARMACEUTICS
`
`APPLICATION FILEABLE?
`
`If the NDA is not fileable from the
`
`product quality-biopharmaceutics
`perspective. state the reasons and
`provide filing comments to be sent
`to the A licant.
`
`N/A
`
`File name: NDA 204592 Product Quality - Biopharmaceutics Filing Review.doc
`
`Page 2
`
`Reference ID: 3267426
`
`

`

`PRODUCT QUALITY - BIOPHARMACEUTICS
`
`FILING REVIEW
`
`
`
`I—fthe NDArs not fileable from the
`
`biopharmaceutics perspective, state
`the reasons and provide filing
`comments to be sent to the
`
`Ay o licant. Are there any potential review
`
`issues to be forwarded to the
`A licant for the 74-da letter?
`
`X
`
`BIOPHARMACEUTICS INITIAL ASSESSMENT
`
`SUMNIARY
`
`roval of
`The applicant Irako Pharmaceuticals submitted a 505(b)(2) NDA application to obtain a
`in
`Zorvolex Capsules 18 mg and 35 mg for the treatment of acute pain ofmild to moderate
`adults. Zorvolex capsules are the reformulation of diclofenac with reduced particle size. The
`reference listed drug for this 505 (b) (2) application is Cataflam® 50 mg (diclofenac potassium
`immediate release tablets, NDA 20142).
`
`
`
`File name: NDA 204592 Product Quality - Biopharmaceufics Filing Review.doc
`
`Page 3
`
`Reference ID: 3267426
`
`

`

`PRODUCT QUALITY — BIOPHARMACEUTICS
`
`FILING REVIEW
`
`|' roposed Dissolution method for Zorvolex capsules
`
`USP
`A taratus
`
`Rotation Medium
`S n eed
`Volume
`
`T
`
`emp
`
`M d'
`e rum
`
`Q= 8% at 20 minute
`
`USP T e I
`yp
`(basket)
`
`100 rpm 900 mL
`
`37°C i0.5°C
`
`10 mM citric acid buffe
`(pH 5 (4)5) with 0.05
`%SLS
`
`Proposed Acceptance Criterion for
`Zorvolex Capsules
`% of the labeled amount dissolved
`
`The tables below show the composition differences in the formulations between the Proof of
`Concept Formulation and Connnercial Formulation for 18 mg and 35 mg strengths.
`
`Overview of the Components of Zorvolex Capsules 18 mg
`Table 2.3.P.2-1
`Used in Clinical Studies
`
`.
`
`_
`
`Initial Phase 1' and
`
`Component Diclofenac
`
`o
`
`A
`
`Lactose monohydrate. NF
`
`(5) (42
`
`IVIicrocrystalline cellulose. NF
`Croscannellose sodium. NF
`
`Sodium latuyl sulfate. NF
`
`Sodium steaiyl fumarate. NF
`
`Purified water. USP'1
`
`
`
`Total (mgt’capsule)
`Abbreviations: NF=Nationa1 Formulary. USP = United States Pharmacopeia. °o\\' w = °o\\'exght weight
`3
`Used in Potggormulation for Initial Phase 1 and Phase 3 111
`(I!) (4)
`
`M“)
`
`File name: NDA 204592 Product Quality - Biophamiaceutics Filing Review.doc
`
`Page 4
`
`Reference ID: 3267426
`
`

`

`PRODUCT QUALITY - BIOPHARMACEUTICS
`
`FILING REVIEW
`
`Overview of the Components of Zorvolex Capsules 35 mg
`Table 2.3.P.2-2
`Used in Clinical Studies
`
`———m
`——"m-m-n
`Diclofenac
`IE-
`'3. —
`Lactose monohydrate, NF
`
`Abbreviations: NF=Nafional Fornmlary, USP= United States Phamacopeia; %w/w—- %weight/weight
`
`File name: NDA 204592 Product Quality - Biopharmaceulics Filing Review.doc
`
`Page 5
`
`Reference ID: 3267426
`
`

`

`PRODUCT QUALITY - BIOPHARMACEUTICS
`FILING REVIEW
`
`
`
`
`02/22/13
` Date
`
`RECOMMENDATION:
`From the ONDQA-Biopharmaceutics perspective, NDA 204592 for Zorvolex Capsules
`(diclofenac) is fileable.
`
`
`
`
`{See appended electronic signature page}
`Banu S. Zolnik, PhD
`Biopharmaceutics Reviewer
`Office of New Drug Quality Assessment
`
`{See appended electronic signature page}
`Sandra Suarez Sharp, Ph.D.
`Secondary Signature
`Office of New Drug Quality Assessment
`
`
`
`02/22/13
` Date
`
`
`
`
`
`
`
`
`
`
`
`
`
`File name: NDA 204592 Product Quality - Biopharmaceutics Filing Review.doc
`
`
`Page 6
`
`Reference ID: 3267426
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BANU S ZOLNIK
`02/27/2013
`
`SANDRA SUAREZ
`02/27/2013
`
`Reference ID: 3267426
`
`

`

`Initial Quality Assessment
`Division of Pre-Marketing Assessment III, Branch VII
`Office of New Drug Quality Assessment
`Division of Anesthesia, Analgesia and Addiction Products
`
`
`
`Anesthesia, Analgesia and Addiction
`204592
`3S
`Iroko Pharmaceuticals, LLC
`December 20, 2012
`October 20, 2013
`NA
`ZorvolexTM Capsules
`18mg and 35 mg Capsules
`Oral
`Management of mild to moderate acute pain
`
`Julia Pinto, Ph.D.
`
`NO
`YES
` √
`
`
`
` √
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`OND Division:
`
`NDA:
`
`
`Chemical Classification
`Applicant:
`
`
`Stamp date:
`
`
`PDUFA Date:
`
`Trademark:
`
`
`Established Name:
`
`Dosage Form:
`Route of Administration:
`Indication:
`
`
`
`Initial Quality Assessment:
`
`
`
`
`
`
`
`
`
`ONDQA Fileability:
`Comments for 74-Day Letter:
`
`
`
`Reference ID: 3266124
`
`

`

`Summary, Critical Issues and Comments
`
`A. Summary
`
`The application is filed as a 505(b)(2), non-priority NDA with 10-month review clock for ZorvolexTM
`Capsules 18 mg and 35 mg for the treatment of mild to moderate acute pain. Zorvolex Capsules are a
`reformulation of diclofenac designed to reduce the particle size (diclofenac
`M0). The
`drug substance is diclofenac acid is supplied by
`(m4) under DIVIF
`(b)«)_ The description of
`the drug substance, the manufacturing process, controls, analytical methods, and specifications of the
`API are referenced to this DMF M”. An LOA is provided.
`
`is prepared in 18mg and 35 mg strengths. Both strengths are
`The drug product, ZorvolexTM capsules,
`from
`(on) white powder encapsulated in hard gelatin capsule shells. The excipients
`used in the composition are all compendial (NF). The container closure system comprises of two
`commercial presentations of 30-count and 90-count HDPE bottles and
`@(leister packages as
`physician samples. Twelve months of real time data for 6 primary batches is provided as support for a
`24— month expiry.
`
`B.
`
`Drug Substance
`
`Molecular Structure, Chemical Name, Molecular Formula and Molecular Weight
`
`Chemical names:
`2-(2-(2.6-dichlorophenylamino)phenyl)acetic acid
`Molecular Formula: C14H11C12N02
`
`CAS: 15307-86—5
`
`MW2 296.15
`
`Cl
`
`N H
`
`Cl
`
`OH
`
`0
`
`(I!)(4)
`
`Drug Substance commercial batches of API will be manufactured and stability tested by
`M0 The release testing of the batches to be used in the preparation of the drug product will be
`done by
`(m4)- The manufacture, quality control and stability are referenced to
`DMF
`(m4) and an LOA is provided.
`
`Potential Impurities and degradation products:
`
`Several process impurities are identified and referenced to DMF M0. Only related substance A is
`present at about (”(0% while the other impurities are detected at below the limit of quantitation of (”(0%-
`
`Drug Substance Specifications:
`
`Drug substance specifications are shown below.
`
`Reference ID: 32661 24
`
`

`

`Table 2.3.5.44 chlofenac Acid Drug Substance Sponsor Specifications
`
`“——
`Amwmmfi-———
`AM
`VII-1
`
`mmmmornm
`
`II
`
`'E .
`
`by
`
`Idenfific‘imhyl-‘I‘IR
`
`mammalian
`USP<197> WWW“
`Win-11mm
`
`III‘I: mmm pathwiflfinOJnimtuofflnmlin
`(WQMQGI)
`pefifixthelefamm
`hi
`.
`
`
`
`
`QM4261
`
`QM4261
`
`QM4261
`
`Alina-imam NMT-Not Mm Th; 9‘".8W
`
`USP<231>MahodII
`
`Reference ID: 32661 24
`
`

`

`Container Closure:
`
`Zorvolex Capsules 18 mg and 35 mg will be stored in 100 cc round HDPE bottles
`. Both strengths will be available in 90-count bottles and 30-count bottles.
`
`
`
`
`
`
`Physician samples of Zorvolex Capsules 18 mg and 35 mg will be packaged as blisters packaged in clear
` film with push through paperback foil. Both strengths will be provided as
` blister packs.
`Respective DMF’s are referenced.
`
`Stability:
`
`Data for three batches of each strength of drug product (total of 6 batches) stored in 30-count, 90-count
`and 3-count blister packages, under long term, intermediate and accelerated conditions is provide.
`Further a regression analysis of an additional 12 months of data is also provided. An expiry of 24
`months is requested.
`
`
`Critical issues for review and recommendation
`C.
`During assessment of the CMC information provided in this NDA, the primary reviewer should consider
`addressing issues identified above and other related ones, summarized here, for their impact on drug
`product quality and performance throughout the shelf-life:
`1. Limits of impurities and related substances in the drug substance as per ICH Q3A(R), in
`consultation with the Toxicology Division and limits of residual solvents for compliance with
`ICH Q3C.
`2. The suitability of the compendial specifications of excipients for drug product manufacturability,
`quality and performance should be assessed.
`3. Details of the manufacturing process of the drug product, e.g.: in-process controls, hold times of
`the compounded solution and manufacturing conditions
`4. Drug product specifications, e.g., impurity/degradant limits as per ICH Q3B(R), impurity limits
`as a structural alert, and unidentified impurity limits, in consultation with the Toxicology
`Division.
`5. The suitability of the analytical methods for related substances and degradation products.
`
`
`D. Recommendation for fileability: The NDA is fileable based on 14 clinical batches and 6 primary
`stability batches with 12 month long term/intermediate and /6-month accelerated stability data
`for drug product packaged in the three proposed presentations. The NDA is suitable for
`evaluation and assessment based on FDA and ICH guidelines for submitting CMC information
`for New Drug Applications.
`
`
`Recommendation for Team Review: The NDA is not recommended for a team review.
`
`
`
`
`
`Reference ID: 3266124
`
`9
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Julia Pinto, Ph.D.
`
`
`
`
`
`
`
`Pharmaceutical Assessment Lead(acting)
`
` Prasad Peri, Ph.D.
`
`
`
` Branch Chief, ONDQA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Feburary 12, 2013
`
`Date
`
` February 12, 2013
`
` Date
`
`
`
`
`
`
`Reference ID: 3266124
`
`10
`
`

`

`NDA Number: 204592
`
`Supplement Number and Type: 3s
`
`Established/Proper Name:
`
`ZorvolexTM Capsules
`
`Appplicant:
`Iroko Pharmaceuticals. LLC
`
`Letter Date: December 20, 2011
`
`Stamp Date: December 20, 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
`
`
`
`B. FACILITIES*
`
`X
`
`NA
`
`Is the CMC section organized
`ade u uatel
`;
`
`Is the CMC section indexed and
`
`paginated (including all PDF files)
`ade a uatel
`;
`
`Are all the pages in the CMC section
`.
`1e ' 1ble?
`
`Has all information requested during
`the IND phase. and at the pre-NDA
`meetin {5 been included?
`
`X
`
`X
`
`X
`
`X
`
`-
`
`2.
`
`3.
`
`4.
`
`-
`
`Is a single. comprehensive list of
`all involved facilities available in
`one location in the a I .lication?
`
`For a naturally-derived API only.
`are the facilities responsible for
`critical intermediate or crude API
`
`manufacturing, or performing
`upstream steps. specified in the
`application? If not. has a
`justification been provided for this
`omission? This question is not
`a u ulicable for s
`I thesized API.
`
`Reference ID: 32661 24
`
`11
`
`

`

`7.
`
`8.
`
`9.
`
`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 iden