CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022567Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`

`

`
`
`ONDQA Division Director’s Memo
`NDA 22-567, VIIBRYD (vilazodone) 10 mg, 20 mg, and 40 mg Tablets
`Date: 07-JAN-2011
`
`Introduction
`
`VIIBRYD (vilazodone) 10 mg, 20 mg, and 40 mg immediate release (IR) film coated
`(FC) tablets are indicated for the treatment of major depressive disorder. This product
`should be titrated with an initial dose of 10mg once daily for 7 days followed by 20mg
`once daily for an additional 7 days. This drug should be taken with food. ONDQA
`recommends approval of this NDA.
`
`Adminstrative
`
`The original submission of this 505(b)(1) NDA was received 22-MAR-2010 from PGx
`Health of New Haven, Connecticut. During the review cycle a CMC amendment dated
`04-NOV-2010 was also reviewed.
`
`The NDA is supported by IND 54,613 and seven drug master files (DMF). Consults for
`EES (26-MAY-2010), PharmTox (16-NOV-2010), Biopharm (06-NOV-2010), and
`DMEPA (for Trade name, 03-NOV-2010) were all acceptable
`
`This NDA is recommended for approval from a Chemistry, Manufacturing and
`Controls standpoint.
`
`Drug Substance (vilazodone hydrochloride)
`
`Chemical Name:
` 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1- piperazinyl]-, hydrochloride (1:1)
`
`
`
`Molecular Formula : C26 H27 N5 O2 x HCl
`
` Molecular Weight : 477.99 (vilazodone HCl) and 441.2 (vilazodone)
`The drug substance is a
` white to cream colored achiral solid manufactured via a
` The drug substance is
`. The pKa is
`7.1 and the aqueous solubility is 0.32 mg/mL. The assigned retest date for the drug
`substance is
`
`
`
`Reference ID: 2888631
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Drug Product VIIBRYD (vilazodone) 10 mg, 20 mg, and 40 mg Tablets
`
`All three strengths are manufactured by
`
`
`
`
`
`
`Excipients used in the formulation are conventional and include lactose, microcrystalline
`cellulose, colloidal silicone dioxide, magnesium stearate and
` film coating.
`
`The
`
` film coat varies according to strength:
`
`
`
`
`The HDPE bottles are sized to accommodate 30, 90, or 500 tablets/bottle. Each bottle
`also contains a 1 gm desiccant canister. The data support the proposed shelf life of 24
`months when stored at room temperature.
`
`Rik Lostritto, Director, ONDQA Division I, DPAMS
`
`
`
`
`
`Reference ID: 2888631
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD T LOSTRITTO
`01/07/2011
`
`Reference ID: 2888631
`
`

`

`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`NDA 22-567
`
`
`Vilazodone 10, 20, 40mg Tablets
`
`PGxHealth, LLC
`
`
`
`Pei-I Chu, Ph.D.
`Office of New Drug Quality Assessment DPA1
`For Division of Psychiatry Drug Products
`
`
`Review of Chemistry, Manufacturing, and Controls
`
`
`
`
`
`
`Reference ID: 2859217
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`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...........................................................................................................................8
`C. CC Block ..........................................................................................................................................9
`Chemistry Assessment..................................................................................... 10
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.10
`S
` DRUG SUBSTANCE [Name, Manufacturer]..........................................................................10
`P
` DRUG PRODUCT [Name, Dosage form] ...............................................................................82
`A
` APPENDICES........................................................................................................................137
`R
` REGIONAL INFORMATION...............................................................................................137
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ..........................138
`A. Labeling & Package Insert ..........................................................................................................138
`B. Environmental Assessment Or Claim Of Categorical Exclusion .................................................141
`
`
`
`Reference ID: 2859217
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Chemistry Review Data Sheet
`
`1. NDA 22-567
`
`2. REVIEW # 1:
`
`3. REVIEW DATE: October 30, 2010
`
`4. REVIEWER: Pei-I Chu, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`None
`
`
`
`
`
`
`
`
`
`
`
`
`
`Document Date
`
`
`
`Document Date
` 22-March-2010
`
`6. SUBMISSION(S) BEING REVIEWED:
`Submission(s) Reviewed
`Original
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`
`PGx Health
`
`Five Science Park
`New Haven, CT 06511
`Kimberly Fabrizio
`
`203-786-3502
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE: N/A
`a) Proprietary Name: TBD
`b) Non-Proprietary Name (USAN): Vilazodone Hydrochloride (vilazodone HCl)
`c) Code Name/# (ONDC only):N/A
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 1
`• Submission Priority: S
`
`Reference ID: 2859217
`
`Page 3 of 147
`
`

`

`
`
`
`
`9. LEGAL BASIS FOR SUBMISSION:
`505(b)(1)
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10. PHARMACOL. CATEGORY: Major Depressive Disorder
`
`
`11. DOSAGE FORM: Tablet
`12. STRENGTH/POTENCY: 10mg, 20mg, 40mg
`
`
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`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:
`Chemical Name: 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-
`piperazinyl]-, hydrochloride (1:1)
`5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride
`
`
`
`
`
`Molecular Formula : C26 H27 N5 O2 x HCl
`Molecular Weight : 477.99 (vilazodone HCl)
`441.2 (vilazodone)
`
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`Reference ID: 2859217
`
`Page 4 of 147
`
`

`

`
`
`
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`
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`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`A. DMFs:
`
`DMF # TYPE HOLDER
`
`ITEM
`REFERENCED
`
`CODE1
`
`STATUS2
`
`DATE
`REVIEW
`COMPLETED
`
`COMMENTS
`
`IV
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`Adequate
`
`10/25/2010
`
`
`
`
`
`
`
`Sufficient
`info provided
`
`Adequate
`
`07/07/2010
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sufficient
`info provided
`
`Sufficient
`info provided
`
`Sufficient
`info provided
`
`Sufficient
`info provided
`
` 1
`
` 4
`
`
` 1
`
` 4
`
` 4
`
`
` 4
`
` 4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 Action codes for DMF Table:
`1 – 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 – Sufficient 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 be reviewed)
`
`Reference ID: 2859217
`
`Page 5 of 147
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`B. Other Documents:
`APPLICATION
`DOCUMENT
`NUMBER
`IND
`54613
`
`
`
`
`
`
`
`DESCRI
`PTION
`Commercial IND
`
`
`
`
`
`
`
`
`I.
`
`
`
`
`
`
`
`
`18. STATUS:
`
`ONDC:
`CONSULTS/
`CMC RELATED
`REVIEWS
`Biometrics
`EES
`Pharm/Tox
`
`Biopharm
`
`LNC
`Methods Validation
`OPDRA
`DMEPA
`EA
`Microbiology
`
`
`
`
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`NA
`acceptable
`Pending (waiting for IR
`response)
`Pending (waiting for
`IR response)
`NA
`NA
`NA
`NA
`NA
`NA
`
`
`5/26/2010
`10/16/2010
`
`
`OC
`Violetta Klimek
`
`10/16/2010
`
`Tien Min Chen
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2859217
`
`Page 6 of 147
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Section
`
`
`
`The Chemistry Review for NDA 22-567
`The Executive Summary
`I. Recommendations
`A. Recommendation and Conclusion on Approvability
`
`
`
`NDA 22567 is recommended approvable from the CMC standpoint. The approval is contingent upon satisfactory
`response from the applicant on the drug substance and drug product questions. A summary of CMC questions is listed at the
`end of this review. Office of compliance has determined that pre-approval inspections for the drug substance, drug product
`and packaging sites are not needed based on profile.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`None as per this review.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`Vilazodone HCl is a dual-acting and selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist. It is thought to
`optimize regulation of 5-HT circuitry at both pre- and postsynaptic sites to augment 5-HT neurotransmission, thereby producing
`an antidepressant effect. Its clinical indication is for the treatment of major depressive disorder. Vilazodone HCl is a new
`chemical entity belonging to the structural chemical group of the indolalkylamines. The full chemical designation is 2-
`benzofurancarboxamide, 5-[4-[4-(5-cyano- 1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1)
`Vilazodone HCl drug substance is a white to cream-colored solid. It is achiral and slightly hygroscopic. Solid state form
`analysis demonstrates that it exists in multiple polymorphs
`).
` form IV
`was chosen for development. The solubility in water is 0.32mg/mL. The partition coefficient between n-octanol and water is
` The pKa is 7.1. The melting point and decomposition starts at ~270ºC.
` by:
`Vilazodone HCl is manufactured,
`ScinoPharm Taiwan, Ltd. (SPT) in Shan-Hua, Taiwan, R.O.C. The drug substance is
`manufactured in a
` A typical batch yield is from
`. The
`resulting drug substance is
`
`
`
`
`
`
`Seven batches of vilazodone HCl manufactured by ScinoPharm Taiwan, Ltd. (SPT) are being
`evaluated on stability. Three batches were manufactured using the intended commercial process.
`All batches were packaged in the container closure intended for commercial material. The
`initial submission included 9 months stability at 25°C/60%RH or for up to 6 months at
`40°C/75%RH. 12 month stability data from the development batches has been provided at the
`mid cycle review period. No significant changes or trends have been observed. However, the
`firm has only provided two 6 month stability data under accelerated storage of 40°C/75% RH
`and 25°C/60%RH using the commercial manufacturing process. The assigned re-test date for
`the drug substance at this point is
` When additional stability data is provided, the re-test
`will be re-assessed.
`
`
`Reference ID: 2859217
`
`Page 7 of 147
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Section
`
`
`
`
`Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are immediate-release, oval, film-coated,
`tablets, manufactured from a
` with total tablet weights of 103 mg, 206 mg and
`412 mg, respectively. The 10 mg tablets are pink; the 20 mg, orange; and the 40 mg, blue. The
`tablets are debossed with the strength on one side and plain on the other. The tablets are
`packaged in appropriately-sized, 30-count, 90-count and 500-count high-density polyethylene
`(HDPE) bottles, and in film/aluminum foil blisters.
`
`The drug product will be manufactured by Patheon Puerto Rico, Inc. (Manati, Puerto Rico). Vilazodone
`HCl Tablets, 10 mg, 20 mg and 40 mg are manufactured from a
`
`process using standard techniques, equipment and controls. Manufacturing comprises of
`
`
`
`
`
`Excipients used in the formulation include lactose, microcrystalline cellulose, colloidal silicone dioxide,
`magnesium stearate and
` film coating.
`
`
`
` for the 10mg, 20mg and 40mg tablets,
` The batch formula for a commercial scale batch is
`which would results in
` 10mg tablets,
` 20mg tablets or
` 40mg tablets.
`Vilazodone HCl tablets may be stored in bulk prior to packaging to accommodate for packaging schedule.
`The HDPE bottles are sized to accommodate 30, 90, or 500 tablets/bottle. Each bottle also contains a 1-g
`desiccant canister. The applicant has submitted 18 month stability data for 6 batches using drug substance
`manufactured by Merck (three each of 10mg and 40mg tablets) and 12 month stability data of drug product
`manufactured with API from Scino Pharm. Based on real time and accelerated stability data at the ICH
`conditions, the 10mg and 40mg tablets are considered stable under proposed storage container closure
`systems. Tablets manufactured with API from SPT have the same stability as those manufactured with
`API from Merck based on comparison of 12-month stability data for SPT-API tablets and Merck-API
`tablets. The data support the proposed shelf life of 24 months when stored at room temperature.
`
`B. Description of How the Drug Product is Intended to be Used
`
`
`This product should be titrated with an initial dose of 10mg once daily for 7 days followed by 20mg once daily for an additional
`7 days. Vilazodone HCl should be taken with food.
`
`
`
`C. Basis for Approvability or Not-Approval Recommendation
`The final approval of this NDA will be based on adequate responses to the Information Request sent to PGx Health Care
`on October 15, 2010.
`III. Administrative
`A. Reviewer’s Signature
`
`Endorsement Block
`Chemist Name: Pei-I Chu, Ph.D./Date: Same date as draft review
`Chemistry CMC Lead:Tom Oliver, Ph.D./Date
`Chemistry Branch Chief Ramesh Sood, Ph.D.
`Chemistry Project Manager Teshara Bouie/Date
`
`
`
`
`Reference ID: 2859217
`
`Page 8 of 147
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`CHEMISTRY REVIEW
`Chemistry Review Section
`
`
`
`
`
`
`
`
`C.
`CC Block
`Orig. NDA-22-567
`
`
`
`Reference ID: 2859217
`
`Page 9 of 147
`
`138 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`X
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PEI-I CHU
`11/03/2010
`
`RAMESH K SOOD
`11/03/2010
`
`Reference ID: 2859217
`
`

`

`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`NDA 22-567
`
`
`Vilazodone 10, 20, 40mg Tablets
`
`PGxHealth, LLC
`
`
`
`Pei-I Chu, Ph.D.
`Office of New Drug Quality Assessment DPA1
`For Division of Psychiatry Drug Products
`
`
`Review of Chemistry, Manufacturing, and Controls
`
`
`
`
`
`
`Reference ID: 2872809
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`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..........................................................9
`C. Basis for Approvability or Not-Approval Recommendation............................................................9
`
`III. Administrative.....................................................................................................................9
`A. Reviewer’s Signature........................................................................................................................9
`B. Endorsement Block...........................................................................................................................9
`C. CC Block ..........................................................................................................................................9
`
`Chemistry Assessment......................................................................................10
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.10
`S
` DRUG SUBSTANCE [Name, Manufacturer]..........................................................................10
`P
` DRUG PRODUCT [Name, Dosage form] ...............................................................................24
`A
` APPENDICES...........................................................................................................................28
`R
` REGIONAL INFORMATION.................................................................................................37
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ............................38
`A. Labeling & Package Insert ............................................................................................................38
`B. Environmental Assessment Or Claim Of Categorical Exclusion ...................................................38
`
`
`
`Reference ID: 2872809
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Chemistry Review Data Sheet
`
`1. NDA 22-567
`
`2. REVIEW # 2:
`
`3. REVIEW DATE: November 30, 2010
`
`4. REVIEWER: Pei-I Chu, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`None
`
`
`
`
`
`
`
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`Submission(s) Reviewed
`Original
`Amendment 17-Quality Response to IR
`
`
`Document Date
`
`
`Document Date
`22-March-2010
`04-November-2010
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`
`PGx Health
`
`Five Science Park
`New Haven, CT 06511
`Kimberly Fabrizio
`
`203-786-3502
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE: N/A
`a) Proprietary Name: Viibryd
`b) Non-Proprietary Name (USAN): Vilazodone Hydrochloride (vilazodone HCl)
`c) Code Name/# (ONDC only):N/A
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 1
`• Submission Priority: S
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2872809
`
`Page 3 of 38
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY: Major Depressive Disorder
`
`
`11. DOSAGE FORM: Tablet
`12. STRENGTH/POTENCY: 10mg, 20mg, 40mg
`
`
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`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:
`Chemical Name: 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-
`piperazinyl]-, hydrochloride (1:1)
`5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride
`
`
`
`
`
`
`
`Molecular Formula : C26 H27 N5 O2 x HCl
` Molecular Weight : 477.99 (vilazodone HCl)
`441.2 (vilazodone)
`
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`Reference ID: 2872809
`
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`A. DMFs:
`
`DMF # TYPE HOLDER
`
`ITEM
`REFERENCED
`
`CODE1
`
`STATUS2
`
`DATE
`REVIEW
`COMPLETED
`
`COMMENTS
`
`IV
`
`III
`
`III
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`III
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`III
`
`III
`
`III
`
`Adequate
`
`10/25/2010
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`
`
`
`
`
`
`Sufficient
`info provided
`
`Adequate
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`07/07/2010
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sufficient
`info provided
`
`Sufficient
`info provided
`
`Sufficient
`info provided
`
`Sufficient
`info provided
`
` 1
`
` 4
`
`
` 1
`
` 4
`
` 4
`
`
` 4
`
` 4
`
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`1 Action codes for DMF Table:
`1 – 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 – Sufficient 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 be reviewed)
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`Reference ID: 2872809
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`Page 5 of 38
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`
`
`APPLICATION
`NUMBER
`54613
`
`DESCRI
`PTION
`Commercial IND
`
`
`
`
`
`B. Other Documents:
`DOCUMENT
`IND
`
`18. STATUS:
`
`
`
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`
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`CONSULTS/
`CMC RELATED
`REVIEWS
`Biometrics
`EES
`Pharm/Tox
`Biopharm
`LNC
`Methods Validation
`OPDRA
`DMEPA
`EA
`Microbiology
`
`
`
`
`
`
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`NA
`acceptable
` acceptable
`acceptable
`NA
`NA
`NA
`Viibryd
`NA
`NA
`
`---
`5/26/2010
`11/16/2010
`11/06/2010
`---
`---
`---
`11/03/2010
` ---
`---
`
`---
`Office of compliance
`Violetta Klimek
`Tien Min Chen
`---
`---
`---
`Loretta Holmes
`---
`---
`
`Reference ID: 2872809
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`Page 6 of 38
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`CHEMISTRY REVIEW
`Chemistry Review Section
`
`
` The Chemistry Review for NDA 22-567
`The Executive Summary
`Recommendations
`A. Recommendation and Conclusion on Approvability
`
`
`I.
`
`
`
`
`NDA 22567 is recommended approval from the perspective of chemistry,
`manufacturing, and controls. . An information request letter was sent to the applicant
`on October 15, 2010. An amendment dated November 04, 2010 included adequate
`quality responses to the CMC issues. The response to the genotoxic impurities is
`found adequate by the Pharmatox reviewer. The biopharm reviewer has also
`determined that the response to the question on dissolution method and dissolution data
`is adequate. All CMC issues have now been adequately resolved.
`Office of compliance has determined the drug substance, drug product and packaging
`facilities are adequate. Pre-approval inspections for the drug substance, drug product
`and packaging sites are not needed based on profile.
`The sponsor has committed to the following actions in the first NDA annual report:
`• Provide a revised
` validation report to demonstrate the limit of quantitation
`for Form IV
`
`Include an updated dissolution method validation report using a stability
`indicating analytical method.
`
`•
`
`
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments,
`Agreements, and/or Risk Management Steps, if Approvable
`
`None as per this review.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Vilazodone HCl is a dual-acting and selective serotonin reuptake inhibitor and 5-HT1A
`receptor partial agonist. It is thought to optimize regulation of 5-HT circuitry at both pre-
`and postsynaptic sites to augment 5-HT neurotransmission, thereby producing an
`antidepressant effect. Its clinical indication is for the treatment of major depressive disorder.
`Vilazodone HCl is a new chemical entity belonging to the structural chemical group of the
`indolalkylamines. The full chemical designation is 2-benzofurancarboxamide, 5-[4-[4-(5-
`cyano- 1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1)
`
`Reference ID: 2872809
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`Page 7 of 38
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`CHEMISTRY REVIEW
`Chemistry Review Section
`
`
`
`
`Vilazodone HCl drug substance is a white to cream-colored solid. It is achiral and slightly
`hygroscopic. Solid state form analysis demonstrates that it exists in multiple polymorphs
`
` form IV was chosen for
`development. The solubility in water is 0.32mg/mL. The partition coefficient between n-
`octanol and water is
`. The pKa is 7.1. The melting point and decomposition starts at
`~270ºC.
` by
`Vilazodone HCl is manufactured,
`ScinoPharm Taiwan, Ltd. (SPT) in Shan-Hua, Taiwan, R.O.C. The drug substance is
`manufactured in a
` A typical batch yield is from
`.
`The resulting drug substance is
` The drug substance is
`
`
`
`
`
`
`
`
`
`
`
`Seven batches of vilazodone HCl manufactured by ScinoPharm Taiwan, Ltd. (SPT) are being
`evaluated on stability. Three batches were manufactured using the intended commercial
`process. All batches were packaged in the container closure intended for commercial
`material. In the IR response dated November 4, 2010, the applicant has committed to
`provide a revised validation report to include
` data in the first NDA annual report.
`
`The initial submission included 9 months drug substance stability data at 25°C/60%RH or for
`up to 6 months at 40°C/75%RH. 12 month stability data from the development batches has
`been provided at the mid cycle review period. No significant changes or trends have been
`observed. However, the firm has only provided two 6 month stability data under accelerated
`storage of 40°C/75% RH and 25°C/60%RH using the commercial manufacturing process.
`The assigned re-test date for the drug substance at this point is
`. When additional
`stability data is provided, the re-test will be re-assessed.
`
`Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are immediate-release, oval, film-coated,
`tablets, manufactured from a
` with total tablet weights of 103 mg, 206 mg and
`412 mg, respectively. The 10 mg tablets are pink; the 20 mg, orange; and the 40 mg, blue.
`The tablets are debossed with the strength on one side and plain on the other. The tablets are
`packaged in appropriately-sized, 30-count, 90-count and 500-count high-density
`polyethylene (HDPE) bottles, and in film/aluminum foil blisters.
`
`The drug product will be manufactured by Patheon Puerto Rico, Inc. (Manati, Puerto Rico).
`Vilazodone HCl Tablets, 10 mg, 20 mg and 40 mg are manufactured from a
`
` process using standard techniques, equipment and controls.
`Manufacturing comprises of
`
` Excipients used in the
`formulation include lactose, microcrystalline cellulose, colloidal silicone dioxide, magnesium
`stearate and
` film coating. The film coat is comprised of:
`
`
` The batch formula for a commercial scale batch is
`
`Reference ID: 2872809
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`Page 8 of 38
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`CHEMISTRY REVIEW
`Chemistry Review Section
`
`
`
`
` 20mg
` 10mg tablets,
`10mg, 20mg and 40mg tablets, which would results in
`tablets or
` 40mg tablets. Vilazodone HCl tablets may be stored in bulk prior to
`packaging to accommodate for packaging schedule. The HDPE bottles are sized to
`accommodate 30, 90, or 500 tablets/bottle. Each bottle also contains a 1-g desiccant canister.
`The applicant has submitted 18 month stability data for 6 batches using drug substance
`manufactured by Merck (three each of 10mg and 40mg tablets) and 12 month stability data
`of drug product manufactured with API from Scino Pharm. Based on real time and
`accelerated stability data at the ICH conditions, the 10mg and 40mg tablets are considered
`stable under proposed storage container closure systems. Tablets manufactured with API
`from SPT have the same stability as those manufactured with API from Merck based on
`comparison of 12-month stability data for SPT-API tablets and Merck-API tablets. The data
`support the proposed shelf life of 24 months when stored at room temperature.
`
`
`
`B. Description of How the Drug Product is Intended to be Used
`
`This product should be titrated with an initial dose of 10mg once daily for 7 days followed by
`20mg once daily for an additional 7 days. Vilazodone HCl should be taken with food.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`This NDA (22-567) is recommended for APPROVAL from the perspective of chemistry,
`manufacturing, and controls. All deficiencies have been adequately resolved.
`
`II. Administrative
`
`A. Reviewer’s Signature
`
`Pei-I Chu, Ph.D.
`
`Endorsement Block
`
`
`
`
`
`
`
`Pei-I Chu, Ph.D.
`Tom Oliver, Ph.D.
`Ramesh Sood, Ph.D.
`Teshara Bouie
`
`
`
`Chemist Name:
`
`Chemistry CMC Lead:
`Chemistry Branch Chief :
`Chemistry Project Manager :
`
`
`
`C. CC Block
`
` Orig. NDA-22-567
`
`
`
`Reference ID: 2872809
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`Page 9 of 38
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`29 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
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`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PEI-I CHU
`12/06/2010
`
`RAMESH K SOOD
`12/06/2010
`
`Reference ID: 2872809
`
`

`

`PRODUCT QUALITY (Small Molecule)
`FILING REVIEW FOR NDA or Supplement (ONDQA)
`
`
`NDA Number: 22567
`
`Applicant:
`
`
`
`
`
`
`
`Supplement Number and Type:
`Original
`
`Established/Proper Name:
`Vilazodone HCl tablets
`
`Letter Date:22-March-2010
`
`Stamp Date: 22-March-2010
`
`
`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:
`
`
`
`1.
`
`2.
`
`Parameter
`Is the CMC section organized
`adequately?
`Is the CMC section indexed and
`paginated (including all PDF
`files) adequately?
`3. Are all the pages in the CMC
`section legible?
`Has all information requested
`during the IND phase, and at the
`pre-NDA meetings been
`included?
`
`4.
`
`GENERAL
`A.
`Yes No
`X
`
`
`
`
`Comment
`
`X
`
`X
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5.
`
`6.
`
`Parameter
`Is a single, comprehensive list of
`all involved facilities available in
`one location in the application?
`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
`applicable for
`API.
`
`FACILITIES*
`B.
`Yes No
`
`x
`
`
`
`
`
`
`
`Comment
`
`
`
`Not Applicable
`
`File name: 090513-Product Qua