`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`022406Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`Attachment 1: Acceptable Facility Inspection
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Application:
`Org. Code:
`Priority:
`Stamp Date:
`PDUFA Date:
`Action Goal:
`District Goal:
`
`NDA 22406000
`161
`15
`28-JUL-2008
`03-JUL-2011
`
`Od-MAY-zott
`
`Sponsor:
`
`JOHNSON AND JOHNSON
`920 US HWY 202 SOUTH
`RARITAN. NJ 068690602
`XARELTO (RIVAROXABAN) ORAL 10 MG
`
`Brand Name:
`Emu. Name:
`RIVAROXABAN
`Generic Name:
`Product Number; Dosage Form; Ingredient; Strengths
`00‘: TABLET. FILM COATED: RNAROXABAN; tOMG
`
`FDA Contacts:
`
`301—796—4246
`Plant: Manager
`T. LAMBERT
`3014963882
`Revmv Chev-mat
`J‘ CRICH
`J BROWN
`‘
`Team Leader
`301-796-1652
`
`Oven" Recommendation:
`ACCEPTABLE
`'
`'
`(5‘) (4)
`by A. INYARD
`()
`ACCEPTABLE
`(5) (4) by JOHNSONE
`
`Esmflltlmm:
`CFN:
`FEI:
`3003228486
`BAYER HEALTHCARE AG
`217-233 FRIEDRICH-EBERT STRASSE
`WUPPERTAL . GERMANY 42117
`
`D"? No:
`
`AADA:
`
`Responsibilities:
`
`mate:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE PACKAGER
`DRUG SUBSTANCE STABILITY TESTER
`NON-STERILE AP! BY CHEMECAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`L... mum”:
`Milestone Date:
`Decision:
`Ream:
`
`oc RECOMMENDATION
`12-JAN-2011
`ACCEPTABLE
`BASED ON FILE REVtEw
`BASED ON PROFILE
`
`
`June 13. 201.1 9:22 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 1 at 2
`
`Continued on next page.
`
`Reference ID: 2959908
`
`

`

`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`
`Chemistry Assessment Section
`
`
`
`
`
`
`Attachment 1: Acceptable Facility Inspection — Continued
`
`FDA CDER EES
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`
`SUMMARY REPORT
`
`3002806462
`
`
`FEI:
`9610135
`CFN:
`
`BAYER SCHERING PHARMA AG
`CHEMPARK
`
`
`
`
`LEVERKUSEN, . GERMANY
`
`
`AADA:
`
`DRUG SUBSTANCE STABILITY TESTER
`
`
`
`FINISHED DOSAGE MANUFACTURER
`
`
`CONTROL TESTING LABORATORIES 'ALSO'
`
`
`
`(DRUGS)
`0C RECOMMENDATION
`
`12-JAN~2011
`
`ACCEPTABLE
`
`‘
`
`BASED ON PROFILE
`
`
`TABLETS, PROMPT RELEASE
`
`
`
`0C RECOMMENDATION
`
`19-JAN-2011
`
`ACCEPTABLE
`
`OAI Status:
`
`NONE
`
`OAI Status:
`
`NONE
`
`Establishment:
`
`DMF No:
`
`Responsibilities:
`
`Profile:
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`Profile:
`
`lug Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`DISTRICT RECOMMENDATION
`
`
`Establishment:
`CFN:
`2650104
`FEI:
`3002942061
`JANSSEN ORTHO LLC.
`CARR # 933 KM 01
`
`
`
`
`
`
`GURABO. PR 00778
`
`
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`Profile:
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`FINISHED DOSAGE MANUFACTURER
`
`
`TABLETS. PROMPT RELEASE
`
`
`QC RECOMMENDATION
`
`OGAPR-2011
`
`ACCEPTABLE
`
`OAI Status:
`
`
`NONE
`
`Reason:
`DISTRICT RECOMMENDATION
`
`
`Establishment:
`CFN:
`2242843
`FEI:
`2242843
`ORTHO—MCNElL-JANSSEN PHARMACEUTICALS INC.
`1125 TRENTON HARBOURTON RD
`
`
`
`
`
`TITUSVILLE. NJ 085601504
`
`
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`Profile:
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`FINISHED DOSAGE STABILITY TESTER
`
`
`
`CONTROL TESTING LABORATORIES 'ALSO'
`
`
`
`(DRUGS)
`0C RECOMMENDATION
`
`08-JUN-20‘l1
`
`ACCEPTABLE
`
`OAI Status:
`
`NONE
`
`Reason:
`DISTRICT RECOMMENDATION
`
`
`
`June 13. 2011 9:22 AM
`
`
`
`
`
`FDA Confidential - lntemal Distribution Only
`
`
`
`
`
`Page 2 of 2
`
`
`
`Reference ID: 2959908
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`This is a representation of an electronic record that was signed
`
`
`
`
`
`
`
`
`
`electronically and this page is the manifestation of the electronic
`signature.
`
`/s/
`“-m-“--—m-u-m“---u-mmm
`
`
`
`JANlCE T BROWN
`06/14l201 1
`
`
`HARIPADA SARKER
`
`06/ 14/201 1
`
`Reference ID: 2959908
`
`
`
`

`

`I U" VUbI\ huh-U
`
`ESTABLISHMENT EVALUATION REQUEST
`
`SUMMARY REPORT
`
`NDA 22406/000
`
`Sponsor:
`
`JOHNSON AND JOHNSON
`
`)Iication
`
`I C~Iez
`
`)r. _
`
`mp Date
`
`JFA Date
`
`Ion Goal
`
`161
`
`1S
`
`28~JUL-2008
`
`03-JUL-2011
`
`920 US HWY 202 SOUTH
`
`RARITAN. NJ 088690602
`
`Brand Name:
`
`XARELTO (RIVAROXABAN) ORAL 10 MG
`
`Estab. Name:
`
`Generlc Name:
`
`RIVAROXABAN
`
`Product Number, Dosage Form; IngradIent; Strengths
`001; TABLET, FILM COATED: RIVAROXABAN; 10MG
`
`Met Goal:
`
`04-MAY-2011
`
`\ Contact:
`
`T. LAMBERT
`
`J. CRICH
`
`Project Manager
`
`Review Chemist
`
`301-796-4246
`
`301-796-3882
`
`J. BROWN
`Team Leader
`301-796-1652
`
`
`uall Recommendation:
`
`ACCEPTABLE
`
`on I
`
`(0(4)
`
`by A. INYARD
`
`()
`
`ACCEPTABLE
`‘
`on
`(5)“)
`by JOHNSONE
`
`
`abIIshmonI:
`
`CFN:
`
`FEI:
`
`3003229486
`
`BAYER HEALTHCARE AG
`217-233 FRIEDRICH-EBERT STRASSE
`
`WUPPERTAL, , GERMANY 42117
`
`AADA:
`
`F No:
`
`iponsIbIIItlos:
`
`DRUG SUBSTANCE MANUFACTURER
`
`DRUG SUBSTANCE PACKAGER
`
`DRUG SUBSTANCE STABILITY TESTER
`
`fllo:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`.g Mllootono:
`
`”to“. pm;
`
`:IsIon:
`
`OC RECOMMENDATION
`
`12-JAN-2011
`
`ACCEPTABLE
`
`noon:
`
`BASED ON FILE REVIEW
`BASED ON PROFILE
`
`
`um 9, 2011 4:12 PM
`
`FDA Confidential — Internal Distribution Only
`
`Page 1 of 2
`
`

`

`I IJn VHI—I‘ I—I—U
`
`
`
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`
`’ SUMMARY REPORT
`
`CFN:
`
`9610135
`
`
`BAYER SCHERING PHARMA AG
`
`
`
`CHEMPARK
`
`FEI:
`
`3002806462
`
`
`
`LEVERKUSEN, , GERMANY
`
`
`DRUG SUBSTANCE STABILITY TESTER
`
`
`
`FINISHED DOSAGE MANUFACTURER
`
`
`CONTROL TESTING LABORATORIES "ALSO"
`
`
`
`(DRUGS)
`OC RECOMMENDATION
`
`
`AADA:
`
`OAI Status:
`
`
`NONE
`
`12-JAN-2011
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`
`TABLETS. PROMPT RELEASE
`
`
`
`
`OC RECOMMENDATION
`19-JAN-2011
`
`I
`
`ACCEPTABLE
`
`OAI Status:
`
`
`NONE
`
`ablishment:
`
`. F No:
`Iponsibilities:
`
`file:
`
`it Milestone:
`
`
`astone Date:
`
`
`:ision:
`
`Ison:
`
`file:
`
`
`:t Milestone:
`astone Date:
`
`
`:ision:
`
`Ison:
`
`DISTRICT RECOMMENDATION
`
`
`
`ablishment:
`
`CFN:
`
`2650104
`
`FEI:
`
`3002942061
`
`JANSSEN ORTHO L.L.C.
`
`
`CARR # 933 KM 0.1
`
`
`
`GURABO, PR 00778
`
`
`
`FINISHED DOSAGE MANUFACTURER
`
`
`
`TABLETS, PROMPT RELEASE
`
`
`
`OC RECOMMENDATION
`
`
`06-APR-2011
`
`ACCEPTABLE
`
`F No:
`
`sponsibilitles:
`
`file:
`
`4 Milestone:
`
`
`astone Date:
`
`
`:ision:
`
`AADA:
`
`OAI Status:
`
`
`NONE
`
`
`DISTRICT RECOMMENDATION
`Ison:
`
`
`abllshment:
`
`CFN:
`
`2242843
`
`FEI:
`
`2242843
`
`F No:
`
`Iponsibilitles:
`
`file:
`
`:t Milestone:
`
`
`astone Date:
`
`
`:lsion:
`
`I80":
`
`ORTHO-MCNEIL—JANSSEN PHARMACEUTICALS INC.
`
`
`1125 TRENTON HARBOURTON RD
`
`
`
`
`TITUSVILLE, NJ 085601504
`
`
`
`AADA:
`
`FINISHED DOSAGE STABILITY TESTER
`
`
`
`CONTROL TESTING LABORATORIES "ALSO"
`
`
`
`(DRUGS)
`OC RECOMMENDATION
`
`
`08-JUN-2011
`
`ACCEPTABLE
`
`OAI Status:
`
`
`NONE
`
`DISTRICT RECOMMENDATION
`
`
`m u
`
`
`
`ne 9, 2011 4:12 PM
`
`FDA Confidential - lntemal Distribution Only
`
`
`
`
`
`Page 2 of 2
`
`
`
`

`

`ONDQA Division Director’s Memo
`NDA 22-406, XARELTO™ (rivaroxaban) Tablets
`10 mg, immediate release, film-coated, tablets
`Date: 16-JUN-2010
`
`Introduction
`
`XARELTO™ (rivaroxaban) film coated immediate release tablets (10 mg) are indicated
`for prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients
`undergoing knee or hip replacement surgery. Dose is once daily beginning after surgery
`once homeostasis has been established; not to exceed 35 days
`
`Adminstrative: This is the second review cycle
`
`On 27-MAY-2010, OND issued a Complete Response letter to the sponsor citing
`unresolved clinical, chemistry, manufacturing and controls (CMC), clinical
`pharmacology and labeling deficiencies that remained to be resolved before the
`application can be approved.
`
`The sponsor submitted a complete response to the CR letter which was received 03-JAN-
`2011. Four additional CMC amendments and one labeling amendment to this response
`were also reviewed as received between 28-APR-2011 and 21-MAY-2011. Also, three
`DMFs were reviewed and found adequate as; one for the drug substance (Bayer
`Healthcare) and two for the drug product (Bayer Healthcare and Janssen-Ortho).
`
`An overall acceptable recommendation was received from the Office of Compliance on
`08-JUN-2011. The ONDQA Biopharm consult was acceptable on 02-MAY-2011
`(dissolution criterion of Q
` in 15 minutes approved)..
`
`No recommendations for any Phase 4 commitments are being made by ONDQA.
`
`ONDQA recommends approval .
`
`Drug Substance: Rivaroxaban
`
`5-Chloro-N-(((5S)-2-oxo-3-[4-(3-oxo-4-moholinyl)phenyl]-l,3-oxazolidin-5-yl) methyl)-
`2-thiophenecarboxamide
`
`
`Molecular Formula: C19H18ClN3O5S M.W.: 435.89
`
`The drug substance is manufactured, tested and packaged by Bayer Schering Pharma.
`
`
`
`Reference ID: 2961987
`
`(b) (4)
`
`

`

`The CMC information for Rivaroxaban drug substance is found in DMF 21581. This
`DMF was previously found to be inadequate to support NDA 22406. Refer to Chemistry
`Review #1 dated 12-MAY-2009. The DMF holder has adequately addressed all
`outstanding deficiencies
`
`Drug Product: XARELTO, Film Coated, Immediate Release Tablets, 10 mg
`
`The uncoated tablet core contains 10 mg of Rivaroxaban as the active pharmaceutical
`ingredient. The drug product is an immediate release formulation containing
`pharmaceutical excipients that are conventional in nature and consists of microcrystalline
`cellulose, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium
`stearate, sodium lauryl sulfate, and Opadry® Pink
`, a proprietary film-coating
`mixture containing polyethylene glycol 3350, hypromellose, titanium dioxide, and ferric
`oxide red.
`
`XARELTO™ Tablets are round, light red, biconvex film-coated tablets marked with a
`triangle pointing down above a “10” on one side, and an “Xa” on the other side and are
`supplied in 75 ml HDPE bottles of 30 tablets (NDC 50458-580-30) and in unit dose (10
`mil
`) blister packs of 10 tablets/strip, 10 strips per carton container
`(NDC 50458-580-10). XARELTO™ Tablets (Rivaroxaban Film-Coated Tablets) are
`manufactured by Schering Pharma under DMF 21581 and Janssen Ortho
`Pharmaceutical under DMF 21592.
`
`The approved expiry is 30 months in the HDPE bottles and 18 months in the
`when stored at USP controlled room temperature.
`
`ONDQA recommends approval.
`
`Richard (Rik) Lostritto, Ph.D., Director
`ONDQA Division I.
`
`blisters
`
`Reference ID: 2961987
`
`(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
`06/16/2011
`
`Reference ID: 2961987
`
`

`

`M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`NDA 22-406
`
`14-Jun-2011
`
`Final CMC recommendation for NDA 22-406
`
`Janice Brown, CMC Lead, DNDQA1/ONDQA
`
`
`TO:
`
`DATE:
`
`FROM:
`
`THROUGH: Richard Lostritto, Ph.D. Director, DNDQA1/ONDQA
`
`SUBJECT:
`
`____________________________________________________________________________
`
`BACKGROUND
`
`This New Drug Application (NDA 22-406, new molecular entity) is for an immediate release 10-
`mg oral tablet of Rivaroxaban (XARELTO) for the prophylaxis of deep vein thrombosis and
`pulmonary embolism in patients undergoing hip replacement surgery or knee replacement
`surgery filed July 29th, 2008, by Johnson & Johnson Pharmaceutical Research and
`Development, L.L.C. on behalf of Ortho- McNeil-Janssen-Pharmaceuticals, Inc. This is the
`second review cycle for this application.
`
`On May 27, 2010 the Division issued a Complete Response letter to the sponsor citing
`unresolved clinical, chemistry, manufacturing and controls (CMC), clinical pharmacology and
`labeling deficiencies that remained to be resolved before the product can be approved. Please
`see the May 12, 2009 Product Quality Review by Josephine Jee, Ph.D. for a complete summary
`of the CMC deficiencies. The sponsor submitted a complete response to the CR letter on
`December 30, 2010 (received on January 03, 2011).
`
`CHEMISTRY, MANUFACTURING AND CONTROL (CMC)
`
`1. Product Quality Review - Product Quality Review of the resubmission was completed by
`Joyce Crich, Ph.D. (May 12, 2011). The resubmission included responses to deficiencies for
`three DMF’s; Bayer DMF 21580 for rivaroxaban 10 mg drug product, Bayer DMF 21581 for
`rivaroxaban drug substance, and J&J DMF 21592 for rivaroxaban 10 mg drug product. The
`NDA also included updated drug substance and drug product information in module 3. The
`CMC review of information in the resubmission concluded that all deficiencies were resolved
`and recommended approval of the NDA, pending an acceptable facility recommendation.
`
`
`
`
`
`
`The Office of Compliance has given an overall acceptable recommendation for the facilities
`on 08-Jun-2011 (see CMC review #3).
`
`Reference ID: 2961195
`
`

`

` No recommendations on Phase 4 commitments were made.
`
`2. Microbiology - The amendment dated May 1, 2009 to DMF 21581 was acceptable from a
`product quality microbiology standpoint (see comment dated February 14, 2011).
`
`
`3. ONDQA Biopharmaceutics - Review of the resubmission was completed by Tapash K.
`Ghosh, Ph.D. (May 02, 2011). The applicant agreed to the dissolution specification of Q =
` in 15 minutes for both Bayer and Johnson & Johnson-manufactured rivaroxaban 10 mg
`drug product, using the dissolution methodology described in the dossier.
`
`
`FINAL CMC RECOMMENDATION
`
`From a CMC perspective, approval of NDA 22-406 is recommended. The action letter should
`include the following statement: “A 30 month shelf life for the drug product in HDPE bottles and
`a 18 month shelf life for the drug product in blisters, when stored at 20°-25°C (68°F - 77°F) or
`room temperature; excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled
`Room Temperature] is granted.”
`
`
`
`Reference ID: 2961195
`
`(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/
`----------------------------------------------------
`
`JANICE T BROWN
`06/15/2011
`
`RICHARD T LOSTRITTO
`06/16/2011
`
`Reference ID: 2961195
`
`

`

`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`
`
`
`NDA 22-406
`
`
`CMC Review # 3
`
`XARELTO (rivaroxaban) Tablets
`
`Johnson & Johnson Pharmaceutical
`Research & Development. L.L.C.
`
`
`
`
`
`Janice Brown, CMC Lead
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`Branch II
`
`
`
`
`Reference ID: 2959908
`
`

`

`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`
`
`
`
`The Chemistry Review for NDA 22-406
`
`The Executive Summary
`
` I. Recommendations
`
`
`A. Recommendation and Conclusion on Approvability
`
`The Office of Compliance has given an overall acceptable recommendation for the
`facilities on 08-Jun-2011 (see attachment 1). CMC agrees with the DMEPA labeling
`recommendations.
`
`From a CMC standpoint, this NDA is recommended for approval.
`
`As noted in CMC review #2, the shelf life for the HDPE bottles and blisters should be
`included in the action letter.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`None
`
`
`Reference ID: 2959908
`
`

`

`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`
`Attachment 1: Acceptable Facility Inspection
`
`
`
`Continued on next page.
`
`Reference ID: 2959908
`
`
`
`
`
`

`

`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`Attachment 1: Acceptable Facility Inspection – Continued
`
`
`
`
`Reference ID: 2959908
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JANICE T BROWN
`06/14/2011
`
`HARIPADA SARKER
`06/14/2011
`
`Reference ID: 2959908
`
`

`

`
`
`
`
`CMC REVIEW
`
`NDA 22-406
`
`CMC Review # 2
`
`
`XARELTO TM (rivaroxaban) Tablets
`
`
`Johnson & Johnson Pharmaceutical
`Research & Development. L.L.C.
`
`
`
`Joyce Z Crich, Ph.D
`
`Review Chemist
`
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`Branch II
`
`
`CMC REVIEW OF NDA 22-406
`For the Division of Hematology Products, OODP/CDER
`
`
`
`
`
`
`
`
`
`Reference ID: 2954863
`
`

`

`
`
`
`
`CMC REVIEW OF NDA 22-406
`
`
`
`Table of Contents
`
`
`CMC Review Data Sheet .........................................................................................5
`
`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....................................................... 12
`C. Basis for Approvability or Not-Approval Recommendation......................................................... 12
`III. Administrative..........................................................................................................................12
`CMC Assessment....................................................................................................14
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.......14
`S. DRUG SUBSTANCE.................................................................................................................... 14
`S.1
`General Information........................................................................ Error! Bookmark not defined.
`S.1.1 Nomenclature............................................................................................................................................. 14
`S.1.2
`Structure..................................................................................................................................................... 15
`S 1.3 General Properties...................................................................................................................................... 15
`S.2
`Manufacture ....................................................................................................................................17
`S.2.1 Manufacturers ............................................................................................. Error! Bookmark not defined.
`S.2.2 Description of Manufacturing Process and Process Controls...................... Error! Bookmark not defined.
`S.2.3
`Control of Materials.................................................................................... Error! Bookmark not defined.
`S.2.4
`Controls of Critical Steps and Intermediates............................................... Error! Bookmark not defined.
`S.2.5
`Process Validation and/or Evaluation ......................................................... Error! Bookmark not defined.
`S.2.6 Manufacturing Process Development ......................................................... Error! Bookmark not defined.
`S.3
`Characterization ..............................................................................................................................17
`S.3.1
`Elucidation of Structure and other Characteristics...................................... Error! Bookmark not defined.
`S.3.2
`Impurities.................................................................................................... Error! Bookmark not defined.
`S.4
`Control of Drug Substance..............................................................................................................17
`S.4.1
`Specification ............................................................................................... Error! Bookmark not defined.
`S.4.2
`Analytical Procedures ................................................................................. Error! Bookmark not defined.
`S.4.3
`Validation of Analytical Procedures ........................................................... Error! Bookmark not defined.
`S.4.4
`Batch Analyses ...........................................................................................Error! Bookmark not defined.
`S.4.5
`Justification of Specification....................................................................... Error! Bookmark not defined.
`S.5
`Reference Standards or Materials ...................................................................................................17
`S.6
`Container Closure System...............................................................................................................17
`S.7
`Stability...........................................................................................................................................17
`S.7.1
`Stability Summary and Conclusions ........................................................... Error! Bookmark not defined.
`S.7.2
`Postapproval Stability Protocol and Stability Commitment........................ Error! Bookmark not defined.
`S 7.3
`Stability Data .............................................................................................. Error! Bookmark not defined.
`P. DRUG PRODUCT ........................................................................................................................ 18
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`Description and Composition of the Drug Product.........................................................................18
`P.1
`Pharmaceutical Development..........................................................................................................18
`P.2
`Components of the Drug Product............................................................................................................... 18
`P.2.1
`P.2.1.1 Drug Substance.............................................................................................................................................. 18
`P.2.1.2 Excipients ...................................................................................................................................................... 18
`P.2.2
`Drug Product.............................................................................................................................................. 19
`P.2.2.1 Formulation Development ............................................................................................................................. 19
`P.2.2.2 Overages........................................................................................................................................................ 19
`P.2.2.3 Physicochemical and Biological Properties................................................................................................... 19
`P.2.3 Manufacturing Process Development ........................................................................................................ 20
`P.2.4
`Container Closure System.......................................................................................................................... 20
`P.2.5 Microbiological Attributes......................................................................................................................... 20
`P.2.6
`Compatibility ............................................................................................................................................. 20
`P.3
`Manufacture ....................................................................................................................................21
`P.3.1 Manufacturers Pending ........................................................................................................................ 21
`P.3.2
`Batch Formula............................................................................................................................................ 22
`P.3.3
`Description of Manufacturing Process and Process Controls..................................................................... 22
`P.3.4
`Controls of Critical Steps and Intermediates.............................................................................................. 22
`P.3.5
`Process Validation and/or Evaluation ........................................................................................................ 22
`P.4
`Control of Excipients ......................................................................................................................23
`P.4.1
`Specifications............................................................................................................................................. 23
`P.4.2
`Analytical Procedures ................................................................................................................................ 23
`P.4.3
`Validation of Analytical Procedures .......................................................................................................... 23
`P.4.4
`Justification of Specifications .................................................................................................................... 24
`P.4.5
`Excipients of Human or Animal Origin ..................................................................................................... 24
`P.4.6
`Novel Excipients........................................................................................................................................ 24
`P.5
`Control of Drug Product .................................................................................................................24
`P.5.1
`Specification .............................................................................................................................................. 24
`P.5.2
`Analytical Procedures ................................................................................................................................ 27
`P.5.3
`Validation of Analytical Procedures .......................................................................................................... 27
`P.5.4
`Batch Analyses .......................................................................................................................................... 27
`P.5.5
`Characterization of Impurities.................................................................................................................... 27
`P.5.6
`Justification of Specification...................................................................................................................... 27
`P.6
`Reference Standards or Materials ...................................................................................................28
`P.7
`Container Closure System...............................................................................................................28
`P.7.1
`System Description .................................................................................................................................... 28
`P.7.2
`Rationale to Selection of Package Components......................................................................................... 29
`P.7.3
`Packaging System Suitability..................................................................................................................... 29
`P.7.3
`Specifications and Methods ....................................................................................................................... 30
`P.8
`Stability...........................................................................................................................................31
`P.8.1
`Stability Summary and Conclusion............................................................................................................ 32
`P.8.2
`Postapproval Stability Protocol and Stability Commitment....................................................................... 33
`P.8.3
`Stability Data ............................................................................................................................................. 33
`A. APPENDICES ............................................................................................................................... 37
`A.1
`Facilities and Equipment (biotech only) .........................................................................................37
`A.2
`Adventitious Agents Safety Evaluation ..........................................................................................37
`A.3
`Novel Excipients.............................................................................................................................37
`R. REGIONAL INFORMATION ...................................................................................................... 37
`R1 Executed Batch Records ......................................................................................................................37
`R2 Comparability Protocols ......................................................................................................................37
`R3 Methods Validation Package ...............................................................................................................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 .................................................. 42
`C. Establishment Evaluation Report................................................................................................... 42
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`III. List Of Deficiencies Communicated and Resolved.................................................................42
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`CMC REVIEW OF NDA 22-406
`CMC Review Data Sheet
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`
`CMC Review Data Sheet
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`
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`1. NDA # 22-406
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: 29-MAY-2011
`
`4. REVIEWER: Joyce Z Crich, Ph. D
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`CMC Review # 1
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`DARRTS
`SD
`Number
`51
`70
`79
`
`Document Date
`12-MAY-2009
`
`Document Date
`
`Stamp Date
`
`21-MAY-2009
`30-DEC-2010
`28-APR-2011
`
`04-May-2011
`10-MAY-2011
`11-MAY-2011
`
`
`21-MAY-2009
`03-JAN-2011
`28-APR-2011
`
`04-May-2011
`10-MAY-2011
`11-MAY-2011
`
`
`80
`82
`83
`N/A
`
`Submission(s) Reviewed
`
`Amendment (CMC information)
`Resubmission/Cass 2
`Amendment (Response to FDA 08-APR-2011 CMC
`IR-Biopharm/dissolution)
`Amendment (Response to 13-APR-2011 EES IR,
`21-APR-2011 LOA’s IR)
`Amendment (container and carton labeling)
`Amendment (Response to 09-MAY-2011 telecon-
`Biopharm & update CMC info)
`Amendment (Revised container and carton labeling)
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Johnson & Johnson Pharmaceutical Research &
`Development. L.L.C.
`920 U.S. Highway 202, P.O.Box 300, Raritan, NJ 00869-
`0602
`Andrea F Kollath, DVM
`(9080 927-6522
`
`Address:
`
`Representative:
`Telephone:
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
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`CMC REVIEW OF NDA 22-406
`CMC Review Data Sheet
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`
`
`a) Proprietary Name: XARELTO™
`b) Non-Proprietary Name: rivaroxaban
`c) Code Name/# (ONDQA only): N/A
`d) Chem. Type/Submission Priority (ONDQA only):
`• Chem. Type: 1
`• Submission Priority: S
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY: Prophylaxis of deep vein thrombosis (DVT)
`and pulmonary embolism (PE) in patients
`undergoing hip or knee replacement surgery.
`
`
`11. DOSAGE FORM: Tablet (Immediate Release Tablets)
`
`12. STRENGTH/POTENCY: 10 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED: √ Rx ___OTC
`
`15. SPOTS (SP