CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`200603
`
`CHEMISTRY REVIEW(S)
`
`
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`
`
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 001
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`

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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`NDA 200-603
`
`
`LATUDA (Lurasidone Hydrochloride) Tablets,
`40 mg and 80 mg
`
`Sunovion Pharmaceuticals, Inc.
`
`
`
`Division of Psychiatry Products, HFD 130
`
`
`
`Shastri Bhamidipati, Ph.D.
`Division of New Drug Quality Assessment I
`Office of New Drug Quality Assessment
`
`Received Date: 30-DEC-2009
`PDUFA Goal Date: 30-OCT-2010
`
`
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`NDA 200-603
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`Latuda (Lurasidone Hydrochloride) Tablets Page 1 of 22
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`Par Pharm., Inc.
`Exhibit 1065
`Page 002
`
`

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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
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`
`
`Table of Contents
`
`
`Table of Contents ................................................................................................................ 2
`Chemistry Review Data Sheet............................................................................................ 3
`The Executive Summary .................................................................................................... 7
`I. Recommendations .......................................................................................................................7
`1. 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 [Lurasidone Hydrochloride, ] ...................................................................................10
`P DRUG PRODUCT [LURASIDONE TABLETS, 40, 80 & 120mg] ............................................................10
`R REGIONAL INFORMATION ....................................................................................................................21
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ..................................21
`A. Labeling & Package Insert...........................................................................................................................21
`III. List Of Deficiencies To Be Communicated.......................................................................22
`
`
`
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`NDA 200-603
`
`Latuda (Lurasidone Hydrochloride) Tablets Page 2 of 22
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 003
`
`

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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
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`
`
`
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`Chemistry Review Data Sheet
`
`
`
`
`1. NDA 200-603
`
`2. REVIEW #: 2
`
`3. REVIEW DATE:26-OCT-2010
`
`4. REVIEWER: Shastri Bhamidipati, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`NDA 200-603 Original Submission
`NDA 200-603 Amendment (SD #6)
`NDA 200-603 Amendment (SD#17)
`
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`NDA 200-603 Amendment (SD#34)
`NDA 200-603 Amendment (SD#37)
`NDA 200-603 Amendment (SD#40)
`NDA 200-603 Amendment (SD#43)
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`Document Date
`30-DEC-2009
`04-MAR-2010
`27-MAY-2010
`
`Document Date
`17-SEPT-2010
`07-OCT-2010
`13-O8T-2010
`18-OCT-2010
`
`Name: Sunovion Pharmaceuticals Inc.
`Address: One Bridge Plaza, Suite 510
`Fort Lee, NJ 07024
`Bridget Walton
`Director, Regulatory Affairs
`Sunovion Pharmaceuticals Inc.
`Telephone: (201) 228-8333
`
`Representative:
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`NDA 200-603
`
`Latuda (Lurasidone Hydrochloride) Tablets Page 3 of 22
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 004
`
`

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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`
`a) Proprietary Name: LURASIDONE
`b) Non-Proprietary Name (USAN): Lurasidone Hydrochloride
`c) Code Name/# (ONDQA only): N/A
`d) Chem. Type/Submission Priority (ONDQA only):
`• Chem. Type: 1
`• Submission Priority: S
`
`Immediate Release Tablets
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: 21 CFR 314.50 , 505(b)(1)
`
`
`10. PHARMACOL. CATEGORY: Psychiatry, Schizophrenia
`
`
`11. DOSAGE FORM:
`
`
`12. STRENGTH/POTENCY: 40 mg and 80 mg tablets
`
`
`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:
`(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)
` Chemical Names:
`
`
`
`
`piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano
`-2Hisoindole-1,3-dione hydrochloride
`
`
`
`
`Molecular Formula: C28H36 N4O2S. HCl
`Molecular Weight: 492.68 Lurasidone free base
`
`
`
`529.14 Lurasidone Hydrochloride salt
`CAS:
`
`[367514-88-3]
`
`
`
`
`
`
`
`
`NDA 200-603
`
`Latuda (Lurasidone Hydrochloride) Tablets Page 4 of 22
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 005
`
`

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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`
`
`Note: The chemical structure presented in Review #1 was replaced with this structure included
`in labeling
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`DMF
`#
`16059
`
`TYPE
`
`II
`
`IV
`
`III
`
`III
`III
`
`III
`
`IV
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`ITEM
`REFERENCED
`Drug substance
`
`HOLDER
`
`Dainippon
`Sumitomo
`Pharma
`
`CODE1
`
`STATUS2
`
`1
`
`4
`
`3,4
`
`3,4
`3,4
`
`3,4
`
`3,4
`3,4
`
`3,4
`
`4
`
`4
`
`3,4
`
`3
`
`3,4
`
`3,4
`
`4
`
`Adequate
`
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`
`DATE
`REVIEW
`COMPLETED
`Aug-27-2010
`
`COMMENTS
`
`Reviewed by S.
`Bhamidipati
`
`
`
`
`
`
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`
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Last reviewed 03-
`Apr-2005
`
`
`
`
`Last reviewed 01-
`Aug-2006
`Last reviewed 31-
`Dec-2008
`Last reviewed 7-
`Jan-2004
`Last reviewed 06-
`Feb-2008
`
`
`
`
`NDA 200-603
`
`Latuda (Lurasidone Hydrochloride) Tablets Page 5 of 22
`
`(b) (4)
`
`(b) (4)
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 006
`
`

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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`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")
`* Solid Oral Dosage form
`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:
`
`
`
`
`
`
`
`APPLICATION NUMBER
`61292
`
`DESCRIPTION
`Lurasidone Hydrochloride tablets
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER(S)
`
`Not applicable
`Overall Acceptable
`Approval recommended
`
`Approval recommended
`Not requested. The methods are
`conventional and do not qualify
`for internal validation by FDA
`labs
`Sponsor proposed trade name
`Latuda was considered
`acceptable.
`Waiver granted
`Not applicable as this is a solid
`oral dosage form
`
`
`
`E. Johnson
`26-OCT-2010
`Sonia Tabocova, Ph.D.
`19-OCT-2010
`Aisar Atrkachi, Ph.D.
`20-OCT-2010
`27-OCT-2010 Houda Mahayni, Ph.D.
`
`
`
`21-OCT-2010 Richard Abate, RPh.
`
`
`
`
`
`
`
`DOCUMENT
`
`IND
`
`18. STATUS:
`ONDQA:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Biometrics
`EES
`Pharm/Tox
`
`Biopharmaceutics
`Methods Validation
`
`DMEPA
`
`EA
`Microbiology
`
`
`19. ORDER OF REVIEW (OGD Only)
`
`
`The application submission(s) covered by this review was taken in the date order of receipt. ____
`Yes ____ No If no, explain reason(s) below:
`
`
`
`NDA 200-603
`
`Latuda (Lurasidone Hydrochloride) Tablets Page 6 of 22
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 007
`
`

`

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`CHEMISTRY REVIEW
`Executive Summary Section
`The Chemistry Review for NDA 200-603
`
`The Executive Summary
`
` I. Recommendations
`
`
`1. Recommendation and Conclusion on Approvability
`
`This NDA for Latuda (Lurasidone Hydrochloride) Tablets (40, and 80 mg) for treatment of
`Schizophrenia is recommended for approval from CMC perspective. However, it should
`be noted that the clinical division is not approving the 120 mg strength tablets. The
`proposed acceptance criteria for dissolution testing (Q30 NLT
`) of the drug product are
`considered not appropriate and the acceptance criterion for dissolution testing should meet
` at 20 minutes. This information was communicated to the applicant and the sponsor
`accepted was accepted the change. The proposed 30 month expiration dating for the drug
`product is supported by the stability data submitted by the sponsor. The Office of
`Compliance has provided an overall acceptable recommendation for the manufacturing and
`the testing facilities. The proposed trade name, Latuda for the drug product was considered
`acceptable by Division of Medication Error and Prevention Analysis. The changes in
`labeling from CMC perspective were also captured at the end of this review.
`
`Notes: This review is an evaluation of sponsor provided response to the IR letter (dated
`20-Aug-2010). Please refer to the review finalized in DARRTS (dated 27-Aug-2010) for
`comprehensive CMC evaluation of this NDA. This NDA was originally submitted by
`Dainippon Sumitomo Pharma America, Inc,. and the rights were transferred to Sepracor,
`Inc. during the course of review process. The name of Sepracor, Inc. was recently
`changed to Sunovion Pharmaceutical Inc.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`
`
`
`
`Not included in this review.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`Drug Product:
`The proposed drug product, Lurasidone consists of the active Lurasidone Hydrochloride, an
`antipsychotropic compound and a new molecular entity in the chemical class of
`benzoisothiazole derivatives. Lurasidone Hydrochloride was developed by Dainippon
`Sumitomo Pharma in collaboration with Merck Research Laboratories (during the initial
`IND stages) for treatment of Schizophrenia. Lurasidone Hydrochloride formulations
`designated Group A and B were used in clinical studies in Japan, Europe and US whereas
`Group C formulation were developed solely for the purpose of commercialization. The
`
`
`
`NDA 200-603
`
`Latuda (Lurasidone Hydrochloride) Tablets Page 7 of 22
`
`(b)
`(4)
`
`(b)
`(4)
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 008
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
`drug product is offered in 40, 80 and 120 mg strengths and each strength is film-coated
`with non-functional but acceptable colors that comply with CFR for use in foods and drugs.
`The drug product is either round shaped biconvex (for 40 mg strength) or oval shaped
`film coated tablet (for 80
` mg strengths) with white film-coating (pale green color
`coat for 80 mg strength) and strength identifying debossing of markings of L40, L80 and
`The commercial formulation contains common pharmaceutical excipients, mannitol,
`pregelatinized starch, hydroxy propyl methyl cellulose
`, croscarmellose, magnesium
`stearate in a dose proportional quantitative composition. The drug product will be
`available as 30 , 90 and 500 count tablets packaged in a
`container with
` child resistant closure with induction seal liner and push
`thru alu-foil blister strips containing 7 or 10 tablets of a given dosage strength.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` A set of six batches of lowest (40 mg) and
` Lurasidone tablets manufactured at development scale without
`debossing and packaged in different configurations and stored at long term storage
`conditions of 25C/60%RH were evaluated for appearance, assay, organic impurities,
`dissolution and
` for stability per ICH guidelines. Stability data obtained were
`statistically assessed for pooling of batches within each set of packaging configuration and
`linear regression analysis was employed for estimation of expiration date. In addition,
`stability data obtained for Lurasidone tablets manufactured at the commercial scale (and
`the facility) for three batches of each strength and packaged as intended for marketing were
`provided up to 6 months. The drug product is recommended to be stored at 25 °C (77 °F)
`with excursions permitted to 15-30 °C (59-86 °F) (USP Controlled Room Temperature).
`
` Drug Substance:
`Lurasidone hydrochloride (Lurasidone HCl) drug substance is a white to off-white
`crystalline powder
`
` the chemical structure of lurasidone HCl (including the absolute
`configuration) was determined to be (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-
`3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2Hisoindole-
`
`
`
`NDA 200-603
`
`Latuda (Lurasidone Hydrochloride) Tablets Page 8 of 22
`
`
`
`
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 009
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
`1,3-dione hydrochloride . Lurasidone HCl has an aqueous solubility of 0.224 mg/mL in
`water with maximum solubility of 0.349 mg/mL in pH 3.5 buffer. Lurasidone
`Hydrochloride, is manufactured by Dainippon Sumitomo Pharma at their Oita plant in
`Japan and the sponsor referred to DMF #16059 through a letter of authorization from the
`DMF holder. The DMF was reviewed and found adequate following DMF holder provided
`response to the deficiencies identified in the initial review. The drug substance is stable for
`36 months when stored at 25°C/60% RH and adequately tested at the drug product
`manufacturing site prior to use.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Latuda (Lurasidone Hydrochloride) tablets of 40 and 80 mg strength will be supplied as
`30 , 90 and 500 count units packaged in a
`
`container with child resistant
` (with induction seal liner )and
`individual push thru alu-foil blisters (7 or 10 count strips). Latuda will be administered
`on once a day schedule, with food, generally beginning with 40 mg. The maximum
`recommended dose is 80 mg once daily. The recommended storage conditions for the drug
`product are: “Store at 25 °C (77 °F) with excursions permitted to 15-30 °C (59-86 °F) (USP
`Controlled Room Temperature).”
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`This NDA for Latuda (Lurasidone Hydrochloride) Tablets (40, and 80 mg) is
`recommended for approval from CMC perspective. A shelf-life of 30 months is
`recommended for expiration dating of the product based on stability data submitted. The
`
`acceptance criterion for dissolution was changed from Q30 NLT
` to Q20 NLT
`based on evaluation of data submitted and in collaboration with Biopharmaceutical
`reviewer. The Office of Compliance has provided an overall acceptable recommendation
`for the manufacturing and the testing facilities.
`
`III. Administrative
`
`
`
`
`
`
`
`
`
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`Chemist Name/Date: Shastri Bhamidipati, Ph.D.
`CMC Lead Name/T. Chhagan
`Project Manager Name: Ann J. Sohn
`
`
`C. CC Block
`
`
`
`Original NDA 200-603
`
`
`DPP(HFD-130)/CSO/A. Sohn
`
`ONDQA/ DNDQAI /PAL/T. Chhagan
`ONDQA/DNDQAI /Brach Chief/R. Sood
`
`DPP (HFD-130)/NDA Division File
`ONDQA/DNDQAI/Chemist/S. Bhamidipati
`ONDQA/DNDQAI RPM/T. Bouie
`
`
`13 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 010
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHASTRI P BHAMIDIPATI
`10/27/2010
`
`RAMESH K SOOD
`10/27/2010
`
`Reference ID: 2856032
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 011
`
`

`

`ONDQA Division Director’s Memo
`NDA 200-603, LATUDA (lurasidone hydrochloride) tablets
`40 mg and 80 mg (strengths correspond to the HCl salt)
`Date: 26-OCT-2010
`
`Introduction
`
`Latuda (lurasidone hydrochloride) immediate release tablets are for the treatment of
`schizophrenia. The strengths of this drug product should have been expressed as the
`neutral species to be in keeping with ONDQA and USP drug product established
`name nomenclature practices and policies.
`ONDQA recommends approval of this NDA.
`
`Administrative
`
`The original submission of this 505(b)(1) NDA was received 30-DEC-2009 from
`Sepracor, Inc., of Fort Lee, NJ. The drug substance is a new molecular entity (NME).
`Two CMC amendments were received on 04-MAY-2010 and 27-MAY-2010 and
`reviewed.
`
`This NDA is supported by IND 61292 and sixteen DMF’s. The consult for the PAI
`(EES) was found to be overall acceptable as of today.
`
`ONDQA recommends approval from the Chemistry, Manufacturing and Controls
`perspective.
`
`
`Drug Substance (lurasidone hydrochloride)
`
`The full chemical name for the drug substance (USAN) is: (3aR,4S,7R,7aS)-2-{(1R,2R)-
`2-[4- (1,2-benzisothiazol-3-yl) piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-
`methano-2Hisoindole-1,3-dione hydrochloride
`Molecular Formula: C28H36 N4O2S. HCl
`
` Molecular Weight:
`492.68 Lurasidone base
`
`
`
`
`529.14 Lurasidone Hydrochloride salt
`CAS: [367514-88-3]
`
`Chemical structure
`
`
`
`
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 012
`
`

`

`Lurasidone hydrochloride drug substance is a white to off-white crystalline powder
`and consists of six chiral centers. The drug substance is obtained in only one
`crystalline form. The absolute stereochemistry is confirmed.
`
`Lurasidone Hydrochloride, is manufactured by Dainippon Sumitomo Pharma at their
`Oita plant in Japan (DMF 16059). The DMF was reviewed and found adequate after
`the DMF Holder provided adequate responses to deficiencies. The drug substance
`is adequately tested at the drug product manufacturing site.
`
`Lurasidone hydrochloride has an aqueous solubility of 0.224 mg/mL in water with
`maximum solubility of 0.349 mg/mL in pH 3.5 buffer.
`
`The approved drug substance retest interval is
`
`
`Drug Product (immediate release tablets).
`
`The drug product is supplied as immediate release tablets. Strengths corresponding to 40
`mg, 80 mg, and 120 mg of lurasidone hydrochloride were developed. For clinical reasons,
`the 120 mg strength will not be approved. The strength of this drug product should
`have been expressed as the neutral species to be in keeping with ONDQA and USP
`drug product established name nomenclature practices and policies.
`
`The commercial formulation contains common pharmaceutical excipients, mannitol,
`pregelatinized starch, hydroxypropylmethyl cellulose
`, croscarmellose,
`magnesium stearate in a dose proportional composition.
`
`
`The manufacturing process consists of
`with magnesium stearate and strength specific color film color and tablet
`shape as follows:
`40 mg strength white film coated round tablets
`80 mg strength pale green film coated oval tablets.
`
`.
`
`
`The drug product will be supplied as 30 , 90 and 500 count tablets packaged in a
` plastic container with
` child resistant closure
`with induction seal liner and push thru aluminum-foil blister strips containing 7 or
`10 tablets of a given strength. A dissolution specification of not less than
` in
`20 minutes is recommended to be approved.
`
`The drug product is to be stored at 25°C (77°F); excursions permitted to 15° to 30°C
`(59° to 86°F) A thirty (30) month drug product expiry is approved for both strengths
`in both bottle and blister package presentations.
`ONDQA recommends approval of this NDA from the CMC perspective.
`
`Rik Lostritto, Director, ONDQA Division I
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 013
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`10/26/2010
`
`Reference ID: 2855329
`
`Par Pharm., Inc.
`Exhibit 1065
`Page 014
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`
`NDA 200-603
`
`
`Lurasidone (Lurasidone Hydrochloride) Tablets,
`40 mg, 80 mg and 120 mg
`
`
`Sepracor, Inc.
`
`
`
`Division of Psychiatry Products, HFD 130
`
`
`
`Shastri Bhamidipati, Ph.D.
`Division of New Drug Quality Assessment I
`Office of New Drug Quality Assessment
`
`Received Date: 30-DEC-2009
`PDUFA Goal Date: 30-OCT-2010
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`NDA 200-603
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`LURASIDONE (Lurasidone Hydrochloride) Tablets Page 1 of 139
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`Par Pharm., Inc.
`Exhibit 1065
`Page 015
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`Table of Contents
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`
`Table of Contents ................................................................................................................ 2
`Chemistry Review Data Sheet............................................................................................ 3
`The Executive Summary .................................................................................................... 7
`I. Recommendations .......................................................................................................................7
`1. 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 [Lurasidone Hydrochloride, ] ...................................................................................10
`P DRUG PRODUCT [LURASIDONE TABLETS, 40, 80 & 120mg] ............................................................12
`R REGIONAL INFORMATION ..................................................................................................................132
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ................................133
`A. Labeling & Package Insert.........................................................................................................................133
`III. List Of Deficiencies To Be Communicated.....................................................................139
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`NDA 200-603
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`LURASIDONE (Lurasidone Hydrochloride) Tablets Page 2 of 139
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`Par Pharm., Inc.
`Exhibit 1065
`Page 016
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`Chemistry Review Data Sheet
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`
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`1. NDA 200-603
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 1-AUGUST-2010
`
`4. REVIEWER: Shastri Bhamidipati, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
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`6. SUBMISSION(S) BEING REVIEWED:
`
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`Document Date
`
`
`
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`Document Date
`30-DEC-2009
`04-MAR-2010
`27-MAY-2010
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`Submission(s) Reviewed
`NDA 200-603 Original Submission
`NDA 200-603 Amendment (SD #6)
`NDA 200-603 Amendment (SD#17)
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`Name: Sepracor Inc.
`
`Address:
`
`One Bridge Plaza, Suite 510
`Fort Lee, NJ 07024
`Bridget Walton
`Director, Regulatory Affairs
`Sepracor Inc.
`
`
`
`Telephone: (201) 228-8333
`
`Representative:
`
`
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`NDA 200-603
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`LURASIDONE (Lurasidone Hydrochloride) Tablets Page 3 of 139
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`Par Pharm., Inc.
`Exhibit 1065
`Page 017
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`a) Proprietary Name: LURASIDONE
`b) Non-Proprietary Name (USAN): Lurasidone Hydrochloride
`c) Code Name/# (ONDQA only): N/A
`d) Chem. Type/Submission Priority (ONDQA only):
`• Chem. Type: 1
`• Submission Priority: S
`
`
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`9. LEGAL BASIS FOR SUBMISSION: 21 CFR 314.50 , 505(b)(1)
`
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`10. PHARMACOL. CATEGORY: Psychiatry, Schizophrenia
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`11. DOSAGE FORM:
`
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`12. STRENGTH/POTENCY: 40 mg, 80 mg and 120 mg tablets
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`13. ROUTE OF ADMINISTRATION: Oral
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`14. Rx/OTC DISPENSED: ___X__ Rx ___OTC
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`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
` SPOTS product – Form Completed
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` X Not a SPOTS product
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`Immediate Release Tablets
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`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4- (1,2-benzisothiazol-3-yl)
` Chemical Names:
`
`
`
`
`piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano
`-2Hisoindole-1,3-dione hydrochloride
`
`
`
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`Molecular Formula: C28H36 N4O2S. HCl
`Molecular Weight: 492.68 Lurasidone free base
`
`
`
`529.14 Lurasidone Hydrochloride salt
`CAS:
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`[367514-88-3]
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`NDA 200-603
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`LURASIDONE (Lurasidone Hydrochloride) Tablets Page 4 of 139
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`Par Pharm., Inc.
`Exhibit 1065
`Page 018
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`ITEM
`REFERENCE
`D
`Drug substance
`
`HOLDER
`
`Dainippon
`Sumitomo
`Pharma
`
`CODE1
`
`STATUS2
`
`1
`
`4
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`3,4
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`3,4
`3,4
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`3,4
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`3,4
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`3,4
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`3,4
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`4
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`4
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`3,4
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`3
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`3,4
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`3,4
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`4
`
`Adequate
`
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`Adequate*
`
`
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`DATE
`REVIEW
`COMPLETED
`Aug-27-2010
`
`COMMENTS
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`Reviewed by S.
`Bhamidipati
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`Last reviewed
`03-Apr-2005
`
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`Last reviewed
`01-Aug-2006
`Last reviewed
`31-Dec-2008
`Last reviewed
`7-Jan-2004
`Last reviewed
`06-Feb-2008
`
`
`A. DMFs:
`DMF
`#
`16059
`
`TYPE
`
`II
`
`IV
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`III
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`III
`III
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`III
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`IV
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`III
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`III
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`III
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`III
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`III
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`III
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`III
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`III
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`III
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`NDA 200-603
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`LURASIDONE (Lurasidone Hydrochloride) Tablets Page 5 of 139
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`(b) (4)
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`(b) (4)
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`Par Pharm., Inc.
`Exhibit 1065
`Page 019
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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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")
`* Solid Oral Dosage form
`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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`B. Other Documents:
`
`DOCUMENT
`
`IND
`
`18. STATUS:
`ONDQA:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Biometrics
`EES
`Pharm/Tox
`Biopharmaceutics
`Methods Validation
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`DMEPA
`
`EA
`Microbiology
`
`APPLICATION NUMBER
`61292
`
`DESCRIPTION
`Lurasidone Hydrochloride tablets
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER(S)
`
`Not applicable
`OC recommendation pending
`Not applicable
` Review pending
`Not requested. The methods are
`conventional and do not qualify
`for internal validation by FDA
`labs
`Proposed trade name was not
`acceptable
`Waiver granted
`Not applicable as this is a solid
`oral dosage form
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`
`
`Dr. Houda Mahayni
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`19. ORDER OF REVIEW (OGD Only)
`
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`The application submission(s) covered by this review was taken in the date order of receipt. ____
`Yes ____ No If no, explain reason(s) below:
`
`
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`NDA 200-603
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`LURASIDONE (Lurasidone Hydrochloride) Tablets Page 6 of 139
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`Par Pharm., Inc.
`Exhibit 1065
`Page 020
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`CHEMISTRY REVIEW
`Executive Summary Section
`The Chemistry Review for NDA 200-603
`
`The Executive Summary
`
` I. Recommendations
`
`
`1. Recommendation and Conclusion on Approvability
`
`This NDA for Lurasidone Tablets (40, 80 and 120 mg) is approvable from CMC
`perspective pending satisfactory responses from the sponsor to the issues identified at the
`end of this review. The proposed acceptance criteria for dissolution testing (Q30 NLT
` of the drug product are considered not appropriate and a final recommendation by
`Biopharmaceutical Reviewer is pending. The proposed 30 month expiration dating for the
`drug product is supported by the stability data submitted by the sponsor. However, any
`changes in dissolution acceptance criteria as recommended by Biopharmaceutical Reviewer
`would also require further evaluation of stability data supporting the expiration dating.
`Additionally, Office of Compliance has not provided a final recommendation as to the
`acceptability of manufacturing and testing facilities for the drug product. It should also be
`noted that this review does not include any labeling changes from CMC perspective since
`the trade names
`) proposed by the sponsor were not considered as
`acceptable by Division of Medication Error and Prevention Analysis.
`Note: This NDA was originally submitted by Dainippon SumitomoPharma America, Inc,.
`and the rights were transferred to Sepracor, In. during the course of review process.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Managemen