`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`202155Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`ONDQA Division Director’s Memo
`NDA 202570, ELIQUIS (Apixaban) Tablets, 2.5 and 5.0 mg
`Date: 22-JUN-2012
`
`
`The NDA for ELIQUIS (Apixaban) film coated tablets (Bristol Myers Squibb) was
`submitted via a 501(b)(1) NDA application (standard review clock). All consults to this
`review have been completed.
`
`The drug substance is adequately characterized and controlled; including Ames positive
`starting materials, impurities, and one intermediate.
`
`The drug product immediate release, film coated tablets (2.5 mg [yellow debossed with
`“893’] and 5.0 mg [pink debossed with “894”]) are packaged for commercial distribution
`in HDPE bottles of 60 or 180 count as well as a 14 count blister package (5.0 mg) for
`physician samples.
`
`An expiry period of 36 months for the commercial packages when stored at USP
`controlled room temperature is approved. For the finished tablets in the bulk container,
`and expiry of 12 months at ICH intermediate condition is also approved.
`
`This NDA is recommended for approval from a Chemistry, Manufacturing and Controls
`standpoint.
`
`Respecfully submitted,
`
`Richard (Rik) Lostritto, Acting Deputy Office Director, ONDQA
`
`Reference ID: 3149696
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`06/22/2012
`
`Reference ID: 3149696
`
`

`

`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`MEMORANDUM
`
`
`
`
`
`
`
`
`
`
`DATE: May 18, 2012
`
`TO: File
`
`THROUGH: Ramesh K. Sood, Ph.D., Branch Chief, ONDQA
`
`FROM: Charles F. Jewell Jr, Ph.D., Sr. Regulatory Review Chemist, ONDQA
`
`SUBJECT: Final Chemistry, Manufacturing and Controls (CMC) Approval Recommendation for
`NDA 202-155 (Apixaban)
`
`On 28 February 2012 the CMC review for the NDA 202-155 (Apixaban) was filed indicating the adequacy
`of the application from the CMC perspective, pending a decision from the Office of Compliance on GMP
`inspection results of the establishments involved in the manufacturing process of apixaban drug substance
`and drug product.
`
`This memo is to confirm the overall acceptable rating based on the GMP inspection results of all the
`pertinent sites, see the detailed report below.
`
`This confirms that NDA 202-155 (Apixaban) is approved from the CMC perspective.
`
`
`Final Establishment Evaluation Report
`
`Reference ID: 3132859
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Application:
`
`Stamp Date:
`
`Regulatory:
`
`Applicant:
`
`NDA 202155/000
`
`28-SEP—201 1
`
`287MAR720’I2
`
`BRISTOL MYERS SOUIBB
`4000
`
`PRINCETON. NJ 085434000
`
`Priority:
`
`Org. Code:
`
`1
`
`110
`
`Action Goal:
`
`District Goal:
`
`28-JAN-2012
`
`Brand Name:
`
`Estab. Name:
`
`ELIQUIS
`
`Generic Name:
`
`APIXABAN
`
`Product Number; Dosage Form; Ingredient; Strength:
`001. TABLET. APIXABAN. 2.56M
`002. TABLET APIXABAN, 5MG
`
`Application Comment:
`
`THIS IS A QUALITY BY DESIGN APPLICATION. CONTACT ONDQA FOR PARTICIPATION ON INSPECTIONS. (on O3-
`OCT—20l 1 by D. HENRY () 30I7964227)
`
`A FORMAL RISK ASSESSMENT WAS CONDUCTED AND
`
`0)“)
`
`FDA Contacts:
`
`D. HENRY
`
`C. JEWELL
`
`K. SRINIVASACHAR
`
`Project Manager
`
`Review Chemist
`
`Team Leader
`
`3017964227
`
`3017964232
`
`3017961760
`
`Overall Recommendation:
`
`ACCEPTABLE
`
`on 27—MAR—20‘I2
`
`by D SMITH
`
`(HFD—323)
`
`3017969643
`
`PENDING
`
`PENDING
`
`0n 04-OCT-201 1
`
`by EES__PROD
`
`on 04-OCT—201 'l
`
`by EES_PROD
`
`Reference ID: 31 32859
`
`

`

`Establishment:
`
`
`
`DMF No:
`
`
`Responsibilities:
`
`
`
`FDA CDER EES
`
`
`
`
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`
`FEI: 3002805546
`
`
`
`
`
`
`CFN: 9610221
`
`
`BRISTOL MYERS SOUIBB
`
`
`
`CONTRADA FONTANA DEL CERASO
`
`
`
`
`ANAGNI, . ITALY
`
`
`
`
`FINISHED DOSAGE PACKAGER
`
`
`
`FINISHED DOSAGE RELEASE TESTER
`
`
`
`
`FINISHED DOSAGE STABILITY TESTER
`
`
`
`
`
`
`AADA:
`
`
`
`Estabiishment
`Comment:
`Profile:
`
`
`
`
`
`
`
`CONTROL TESTING LABORATORIES "ALSO" (DRUGS)
`
`
`
`
`
`
`
`OAI Status:
`
`
`
`
`NONE
`
`TABLETS, PROMPT RELEASE
`
`
`
`
`
`NONE
`
`
`
`
`
`Planned Comgletion Decision
`Reguest Txge
`Milestone Date
`Milestone Name
`
`
`
`
`
`
`
`
`
`cm‘ment— Reason
`
`SUBMITTED TO OE:
`04—OCT—20‘I1
`
`
`
`
`
`
`
`06—OCT—20'I1
`Product Specific
`SUBMITTED TO DO
`
`
`
`
`
`OBD SITE - PLS SEE APPLICATION COMMENTS REGARDING RTR
`
`
`
`
`
`
`
`
`
`
`
`ASSIGNED INSPECTION TO “3
`
`
`
`
`
`
`UGPOCTPQO’I’I
`
`
`GMP Inspecllon
`
`
`
`
`INSPECTION SCHEDULED
`
`
`
`
`’IS—FEB—2012
`
`
`
`UB—MAR—2012
`
`
`
`
`Creator
`
`
`HENRYD
`
`
`
`SMITH DE
`
`
`
`
`PHILPYE
`
`
`
`IRIVERA
`
`
`
`BRYKMANR
`
`
`
`DO RECOMMENDATION
`2Y—MAR-2U’I2
`
`
`
`FACILITY ACCEPTABLE RECOMMENDATION IS ONLY PROVIDED FOR THE REFERENCED
`
`
`
`
`
`
`
`
`APPLICATIONS. FACILITY OVERALL ACCEPTABILITY IS PENDING RECEIPT OF EIR AND
`
`
`
`
`
`
`
`
`
`ACCOMPANYING DOCUMENTATION.
`
`OC RECOMMENDATION
`
`
`
`ZTEMARQOIQ
`
`
`
`
`
`
`ACCEPTABLE
`
`INSPECTION
`
`
`
`
`
`ACCEPTABLE
`SMITH DE
`
`
`DISTRICT RECOMMENDATION
`
`
`
`
`
`
`SUBMITTED TO CIC
`
`
`
`
`
`U4—OCT-20'I1
`
`
`
`US—OCT-ZO'H
`GMP Inspectlon
`SUBMITTED TO DO
`
`
`
`
`
`
`LAST El COVERING TCM PROFILE WAS 2003, THIS EER IS FOR PACKAGING WHICH IS NOT
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`OBD RELATED — PS CRITERIA IS FOR RELEASE TESTING AS SUBMITTED IN EER FOR CTL
`
`
`
`
`
`
`
`
`
`
`
`
`
`PROFILE AS GSIGMP INSPECTION
`
`
`
`
`
`
`
`
`ASSIGNED INSPECTION TO IB
`
`
`
`
`
`
`USEOCTEZO‘II
`
`
`GMP Inspection
`
`
`
`
`INSPECTION SCHEDULED
`
`
`
`
`’IEEFEBEZUIQ
`
`
`
`OBEMARE2012
`
`
`ACCEPTABLE
`
`INSPECTION
`
`
`
`
`
`
`
`HENRYD
`
`
`
`SMITH DE
`
`
`
`
`PHILPYE
`
`
`
`IRIVERA
`
`
`
`
`BRYKMANR
`
`
`
`
`
`DO RECOMMENDATION
`2?—MAR-2U’I 2
`
`
`
`FACILITY ACCEPTABLE RECOMMENDATION IS ONLY PROVIDED FOR THE REFERENCED
`
`
`
`
`
`
`
`
`APPLICATIONS. FACILITY OVERALL ACCEPTABILITY IS PENDING RECEIPT OF EIR AND
`
`
`
`
`
`
`
`
`
`ACCOMPANYING DOCUMENTATION.
`
`OC RECOMMENDATION
`
`
`
`27—MAR-2O T 2
`
`
`
`
`ACCEPTABLE
`SMITH DE
`
`
`DISTRICT RECOMMENDATION
`
`
`
`
`May 18, 2012 3:49 AM
`
`
`
`
`
`
`FDA Confidential - Internal Distribution. Only
`
`
`
`
`
`
`Page 2 of 7
`
`
`
`
`
`Reference ID: 3132859
`Reference ID: 3132859
`
`

`

`Establishment:
`
`
`
`DMF No:
`
`
`Responsibilities:
`
`
`
`FDA CDER EES
`
`
`
`
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`
`FEI: 2623458
`CFN: 2623458
`
`
`
`
`BRISTOL MYERS SQUIBB MANUFACTURING COMPANY
`
`
`
`
`RD #3 KM 7?,5
`
`
`
`
`HUMACAO. PR DDYQ’I
`
`
`
`
`
`AADA:
`
`
`
`
`
`
`
`FINISHED DOSAGE MANUFACTURER
`
`
`
`FINISHED DOSAGE RELEASE TESTER
`
`
`
`
`FINISHED DOSAGE STABILITY TESTER
`
`
`
`
`
`Estabiishment
`Comment:
`Frofiie:
`
`
`
`
`
`
`
`TABLETS, PROMPT RELEASE
`
`
`
`
`OAI Status:
`
`
`
`
`NONE
`
`
`
`
`
`Milestone Name
`
`Comment
`
`SUBMITTED TO DC
`
`
`
`
`
`Milestone Date
`
`
`
`
`Reguest nge
`
`
`
`U4AOCT7201‘I
`
`
`
`Planned Comeletion Decision
`
`
`Reason
`
`
`
`Product Specific
`UB—OCT-201 1
`SUBMITTED TO DO
`
`
`
`
`
`QBD APPLICATION , PLS SEE APPLICATION COMMENTS
`
`
`
`
`
`
`
`
`
`ASSIGNED INSPECTION TO “3
`
`
`
`
`
`
`12—DEC-20'I'I
`
`
`Product Specific
`
`
`
`
`INSPECTION SCHEDULED
`
`
`
`
`12—DEC-201'I
`
`
`
`30—JAN—2012
`
`
`ACCEPTABLE
`
`INSPECTION
`
`
`
`Creator
`
`
`HENRYD
`
`
`
`SMITHDE
`
`
`
`
`RHERNAND
`
`RHERNAND
`
`RHERNAND
`
`
`
`
`
`
`
`
`
`
`
`DO RECOMMENDATION
`13—FEB—20'I2
`
`
`
`ACCEPTABLE RECOMMENDATION BASED ON INSPECTIONAL RESULTS. ESTABLISHMENT
`
`
`
`
`
`
`
`INSPECTION CONDUCTED FROM JANUARY 23. 2OI2 TO FEBRUARY 2‘ 2012 AND CLASSIFIED
`
`
`
`
`
`
`
`
`
`
`NAI
`
`OC RECOMMENDATION
`
`
`
`
`13—FEB-2D’I2
`
`
`INYARDA
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`
`
`May 18, 2012 3:49 AM
`
`
`
`
`
`
`FDA Confidential - internal Distribution Only
`
`
`
`
`
`
`Page 3 of 7
`
`
`
`
`
`
`
`Reference ID: 3132859
`Reference ID: 3132859
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Establishment:
`
`CFN;
`
`1825662
`
`FEI: 1825662
`
`BRISTOL-MYERS SQUIBB COMPANY, INC.
`4601 HIGHWAY 62 E
`MOUNT VERNON. IN 476209682
`
`AADA:
`
`FINISHED DOSAGE MANUFACTURER
`FINISHED DOSAGE PACKAGER
`
`FINISHED DOSAGE RELEASE TESTER
`
`FINISHED DOSAGE STABILITY TESTER
`
`TABLETS, PROMPT RELEASE
`
`OAI Status: NONE
`
`DMF No:
`
`Responslbllltles:
`
`Establishment
`Comment:
`Profile:
`
`Planned Comeletion Decision
`Reguest TIE
`Milestone Date
`Milestone Name
`W— Reason
`SUBMITTED TO OC
`04-OCT-2011
`
`OB-OCT—2011
`SUBMITTED TO DO
`QBD SITE - PLS SEE APPLICATION COMMENTS
`
`Product Specific
`
`ASSIGNED INSPECTION TO IB
`0M4). INSPECTION
`
`PAT
`DISTRICT GOAL 1/28'2012
`
`06-OCT-2011
`
`Product SpeCIfiC
`
`ASSIGNED INSPECTION TO IB
`
`DIS-OCT-ZD'I'I
`
`Product Specific
`
`Creator
`
`HENRYD
`
`SMITHDE
`
`PDOMINGO
`
`PDOMINGO
`
`DO RECOMMENDATION
`
`02-FEB—2012
`
`ACCEPTABLE
`
`DOMBROWSKIR
`
`PS PREAPPROVAL El OF FIRM (DATED 1/17-24’ 12 FOR APPL 202155) CLASSIFIED VAI, SITE
`APPROVAL RECOMMENDED
`
`INSPECTION
`
`OC RECOMMENDATION
`
`OZ-FEB—ZOIZ
`
`STOCKM
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`
`
`May 18, 2012 8:49 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 4 of 7
`
`Reference ID: 31 32859
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Establishment:
`
`CFN:
`
`(b) (4)
`
`FEI:
`
`lb) (4)
`
`Mil)
`
`)
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE
`
`(”(4)
`
`Establishment
`Comment:
`Profile:
`
`mm (on mom-2011 by
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAl Status:
`
`MW)
`NONE
`
`Reguest Tm Planned Comgletion Decision
`Milestone Date
`Milestone Name
`50mm— Reason
`SUBMITTED TO GO
`O4—OCT-2011
`
`00 RECOMMENDATION
`
`06—OCT—2011
`
`ACCEPTABLE
`BASED ON PROFIIL
`
`Creator
`
`mm)
`
`(b) (4)
`
`
`
`May 18, 2012 8:49 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 5 of 7
`
`Reference ID: 31 32859
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Establishment:
`
`CFN:
`
`(”(4)
`
`FEI:
`
`ID) (4)
`1b) (4)
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE
`
`(m4)
`
`Establishment
`Comment:
`Profile:
`
`mm (on 03-OCT-2011 by
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`man
`NONE
`
`Milestone Name
`Comment
`SUBMlTTED T0 00
`
`Milestone Date
`
`Rguest TIE
`
`04-OCT-201'l
`
`Planned Comgletion Decision
`Reason
`
`SUBMITTED TO DO
`PERFORMS
`
`10—Day Letter
`OB-OCT—201 1
`00(4) - ONDQA HAS NOT INDICACTED THIS AS A QBD SITE
`
`UNDER REVIEW
`
`06-OCT-2011
`
`DO RECOMMENDATION
`
`13-DEC-2011
`
`OC RECOMMENDATION
`
`14083201 1
`
`Creator
`
`M“)
`
`0)“)
`
`PHILPYE
`
`STOCKM
`ACCEPTABLE
`BASED ON FILE REVIEW
`
`INYARDA
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`May 18, 2012 8:49 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 6 of 7
`
`Reference ID: 31 32859
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Establishment
`
`CFN: 9610172
`
`FEI: 3002806583
`
`SWORDS LABORATORIES LTD DIV OF BRISTOL MYERS SQUIBB
`
`DMF No:
`
`Responsibilities:
`
`WATERY LANE
`SWORDS. DUBLIN, . IRELAND
`
`AADA:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE RELEASE TESTER
`
`0
`.
`Esgflmmem
`Profile:
`
`0M4) ESTABLISHED FOR THE DRUG SUBSTANCE PROCESS (on 030CT-2011 by D. HENRY () 3017964227)
`NON—STERILE API BY CHEMICAL SYNTHESIS
`OAI status:
`NONE
`
`Mllostone Name
`Comment
`SUBMITTED TO 00
`
`Milestone Date
`
`guest 71E
`
`04*OCT72011
`
`Planned Comgletlon Decision
`Reason
`
`SUBMITTED TO DO
`OBD SITE -
`
`Product Specmc
`06—OCT-2011
`(5)“) ESTABLISHED - PLS SEE APPLICATION COMMENTS
`
`UNDER REVIEW
`
`06-OCT-2011
`
`DO RECOMMENDATION
`
`31~OCT~2011
`
`0C RECOMMENDATION
`
`31-OCT—20I l
`
`Creator
`
`HENRYD
`
`SMITHDE
`
`PHILPYE
`
`STOCKM
`ACCEPTABLE
`BASED ON FILE REVIEW
`
`STOCKM
`ACCEPTABLE
`DISTRICT RECOMMENDATTON
`
`May 18, 2012 8:49 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 7 of 7
`
`Reference ID: 31 32859
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CHARLES F JEWELL
`05/18/2012
`
`RAMESH K SOOD
`05/18/2012
`
`Reference ID: 3132859
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`METHODS VALIDATION REPORT SUMMARY
`
`TO:
`
`
`
`
`Charles Jewell and William Adams, CMC Reviewer
`Office of New Drug Quality Assessment (ONDQA)
`E-mail Address: charles.jewell@fda.hhs.gov; William.adams@fda.hhs.gov
`Phone: (301)-796-4232 and (301)-796-1321
`Fax:
`(301)-796-9747
`
`FROM: FDA
`
`Division of Pharmaceutical Analysis
`James Allgire, Team Leader
`Suite 1002
`1114 Market Street
`St. Louis, MO 63101
`Phone: (314) 539-3813
`
`
`
`
`Through: Benjamin J. Westenberger, Deputy Director
` Phone: (314) 539-3869
`
`SUBJECT: Methods Validation Report Summary
`
`
`
`Application Number: NDA 202155
`
`
`
`
`Name of Product: Eliquis (apixaban) Tablets, 2.5 mg and 5 mg
`Applicant: Bristol-Myers Squibb Company
`Applicant’s Contact Person: Porter P. Layne, group Director, GRS
`Address: P.O. Box 4000, Princeton, NJ 08543-4000
`
`Telephone: 609-252-4722
`
`
`
`
`
`Fax: 609-252-6000
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date Methods Validation Consult Request Form Received by DPA: 12/08/11
`Date Methods Validation Package Received by DPA: 12/08/11
`
`Date Samples Received by DPA: 12/23/11
`Date Analytical Completed by DPA: 03/12/12
`
`Laboratory Classification: 1. Methods are acceptable for control and regulatory purposes.
`
`2. Methods are acceptable with modifications (as stated in accompanying report).
`
`3. Methods are unacceptable for regulatory purposes.
`
`
`
`Comments:
`
`
`
` Cover memo and summary of results are attached.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3101163
`
`
`
`
`
`
`
`
`
`
`Page 1 of 3
`
`
`
`
`
`
`
`
`
`Version: 7/13/2011
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`Food and Drug Administration
`
`
`
`
`Center for Drug Evaluation and Research
`Division of Pharmaceutical Analysis
`St. Louis, MO 63101
`Tel. (314) 539-3815
`
`
` March 12, 2012
`
`
`
` Charles Jewell, Review Chemist (HFD-800)
` William Adams, Review Chemist (HFD-800)
`
`Date:
`
`To:
`
`
` Through: B. J. Westenberger, Deputy Director, Division of Pharmaceutical Analysis,
`
`
`
`(HFD-920)
`
`From: Michael Trehy, Chemist (HFD-920)
`
`Subject: Method Validation for NDA 202155
`
` Eliquis® Apixaban 2.5 mg tablets
`
`The following methods were evaluated and are acceptable for quality control and regulatory purposes:
`
`
`• 95011145 Apixaban Tablets – Identification, Potency and Content Uniformity (HPLC) and
`method
`• 95011189 Apixaban Tablets – Potency, Impurities/Degradants, Identification (HPLC)
`
`The Division of Pharmaceutical Analysis (DPA) has the following comment pertaining to this method.
`
` typographical error on page 9 of method 95011145 was found.
`
`
`
` A
`
`
`
`
`
`
`
`
`Reference ID: 3101163
`
`
`
`
`
`
`
`
`
`
`Page 2 of 3
`
`
`
`
`
`
`
`
`
`Version: 7/13/2011
`
`(b) (4)
`
`

`

`
`
`Summary of Results
`
`
`
`
`%
`
`
`
`
`
`NDA 202155
`
`
`
`
`
`
`
`
`
`% limit
`
`
`
`
`
`Method: 95011145 Apixaban Tablets – Identification, Potency and Content Uniformity (HPLC)
` Identity: relative retention time of sample to standard
`
` Potency:
`%
` Content uniformity % label claim:
`
`
` acceptance value
`
`Method: 95011189 Apixaban Tablets – Potency, Impurities/Degradants, Identification (HPLC)
` Identity: relative retention time of sample to standard
`
`%
` Potency:
` limit
` % Impurities: prep-1 prep-2 avg(2) Limit
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3101163
`
`
`
`
`
`
`
`
`
`
`Page 3 of 3
`
`
`
`
`
`
`
`
`
`Version: 7/13/2011
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(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/
`----------------------------------------------------
`
`JAMES F ALLGIRE
`03/13/2012
`
`BENJAMIN J WESTENBERGER
`03/15/2012
`
`Reference ID: 3101163
`
`

`

`
`
`NDA 202,155
`
`Eliquis®
`(Apixaban Tablets, 2.5mg & 5.0mg)
`
`Bristol-Myers Squibb
`
`Charles Jewell (Drug Substance)
`William M. Adams (Drug Product)
`(I!) (4)
`Yong Wang (
`methods)
`Office of New Drug Quality Assessment
`
`For the Division of Cardiorenal Products
`
`Reference ID: 3093460
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`CMC Review Data Sheet .........................................................................................4
`
`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 CMC 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 .................................................. 11
`
`C. Basis for Approvability or Not—Approval Recommendation ................................................... 11
`
`III. Administrative ...................................................................................................................... 11
`
`CMC Assessment.................................................................................................... 13
`
`I. Review Of Common Technical Document-Quality (Ctd—Q) Module 3.2: Body Of Data 14
`
`S DRUG SUBSTANCE ................................................................................................................... 14
`8.1
`General Information ..................................................................................................................... 14
`8.2
`Manufacture .................................................................................................................................. 14
`8.3
`Characterization............................................................................................................................ 15
`
`8.4
`5.5
`
`8.6
`8.7
`
`Control of Drug Substance ........................................................................................................... 15
`Reference Standards or Materials ...............................................................................................21
`
`Container Closure System ............................................................................................................21
`Stability ..........................................................................................................................................21
`
`P DRUG PRODUCT ....................................................................................................................... 21
`
`P.1
`P.2
`R3
`
`PA
`P.5
`R6
`
`R7
`P.8
`
`Description and Composition of the Drug Product....................................................................21
`Pharmaceutical Development ......................................................................................................21
`Manufacture ..................................................................................................................................25
`
`Control of Excipients ....................................................................................................................27
`Control of Drug Product ..............................................................................................................27
`Reference Standards or Materials ...............................................................................................31
`
`Container Closure System ............................................................................................................31
`Stability ..........................................................................................................................................32
`
`A APPENDICES ............................................................................................................................. 32
`
`A.1
`A.2
`A3
`
`Facilities and Equipment (biotech only)......................................................................................32
`Adventitious Agents Safety Evaluation .......................................................................................32
`Novel Excipients ............................................................................................................................32
`
`R REGIONAL INFORMATION .................................................................................................. 32
`
`CMC Review 01
`
`Reference ID: 3093460
`
`Page 2 of 33
`
`

`

`
`
`R1 Executed Batch Records....................................................................................................................32
`
`R2 Comparability Protocols ...................................................................................................................33
`R3 Methods Validation Package ............................................................................................................33
`
`II. Review Of Common Technical Document-Quality (Ctd—Q) Module 1 .............................33
`
`A. Labeling & Package Insert.......................................................................................................... 33
`
`B. Environmental Assessment 01' Claim 0f Categorical Exclusion ............................................ 33
`
`III. List Of Deficiencies to be Communicated............................................................................33
`
`CMC Review 01
`
`Reference ID: 3093460
`
`Page 3 of 33
`
`

`

`
`
`CMC Review Data Sheet
`
`CMC Review Data Sheet
`
`1.
`
`NBA 202,155
`
`2.
`
`3.
`
`4.
`
`REVIEW #2
`
`REVIEW DATE: 27 Feb 2012
`
`REVIEWER: Charles Jewell, Ph.D. (drug substance)
`William M. Adams (drug product)
`Yong Wang, Ph.D. ( two methods)
`
`5.
`
`PREVIOUS DOCUMENTS:
`
`N-002 Amendment (CMC RU)
`N—004 Amendment (updated CMC RU)
`mm Letter (CMC)
`IQP Memo
`PQM Memo to OC (API)
`N—017 Amendment (response to IR 01 Letter)
`PQM Memo to OC (DP)
`IR 02 Letter (Biopharm)
`N-023 Amendent (response to IR 02 Letter)
`IR 03 Letter (CMC/Biopharm)
`CMC Review 01
`
`03 Nov 2010
`30 Sep 2011
`17 Nov 2011
`07 Nov 2011
`08 Nov 2011
`09 Dec 2011
`07/Dec 2011
`16 Dec 2011
`23 Dec 2011
`03 Feb 2012
`15 Feb 2012
`
`6.
`
`SUBNIISSION(S) BEING REVIEWED:
`
`Telcon regarding IR 03 Letter
`N—042 Amendment (response to IR 03 Letter)
`N—047 Amendment (follow-up CMC information)
`
`(08 Feb 2012)
`14 Feb 2012
`27 Feb 2012
`
`7.
`
`NANIE & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Representative:
`Telephone:
`
`Bristol-Myers Squibb
`PO Box 4000
`Pnnceton, NJ 08543-4000
`Porter P. Layne, MBA, Group Director, GRS
`(609) 252-4722
`
`8.
`
`DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):
`c) Code Name/# (ONDQA only):
`
`Eliquis
`Apixiban
`——
`
`CMC Review 01
`
`Reference ID: 3093460
`
`Page 4 of 33
`
`

`

`
`
`CMC Review Data Sheet
`
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type:
`
`0 Submission Priority:
`
`1
`
`S
`
`9.
`
`LEGAL BASIS FOR SUBMISSION: 505(b)(l)
`
`l0.
`
`PHARMACOL. CATEGORY: Anticoagulant
`
`11.
`
`DOSAGE FORM: Fihn—Coated Tablet
`
`12.
`
`STRENGTH/POTENCY: 2.5mg and 5.0mg
`
`l3.
`
`ROUTE OF ADNIINISTRATION: Oral
`
`14.
`
`Rx/OTC DISPENSED:
`
`\l Rx
`
`OTC
`
`15.
`
`SPOTS {SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`
`‘1
`Not a SPOTS product
`
`l.
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`Chemical Name
`
`Molecular Fonnula
`Molecular Weight
`Molecular Structure
`
`1-(4-methoxyphenyl)—7—oxo-6—[4-(2-oxopiperidin-1-yl)phenyl]-4,5_,6,7—
`tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
`C25H25N504
`459.5 amu
`
`
`
`/
`lh‘ "
`
`17.
`
`RELATED/SUPPORTING DOCUNIENTS:
`
`A.
`
`Supporting DNIFs:
`
`
`Date Review
`
`
`
`Comments”
` Item Referenced
`Com I leted
`
`
`0’) (4)
`
`
`
`CMC Review 01
`
`Reference ID: 3093460
`
`Page 5 of 33
`
`

`

`
`
`CMC 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")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF
`did not need to be reviewed)
`3 Include reference to location in most recent CMC Review
`
`B.
`
`Other Supporting Documents: None
`
`18.
`
`CONSULTS/CMC-RELATED REVIEWS:
`
`STATUS/
`COMMENTS
`REVIEWER
`SUBJECT
`CONSULTS
`E_———_
`————_
`————
`————
`24Feb2012 m—
`oweczou
`
`ans/own
`
`exclusion
`
`Validation
`
`__—-_
`———-—
`
`Louis
`
`CMC Review 01
`
`Reference ID: 3093460
`
`Page 6 of 33
`
`

`

`
`
`Executive Summary Section
`
`The CMC Review for NBA 202,155
`
`The Executive Summary
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`From the CMC perspective, the application is found to be adequate, pending a decision from the
`Office of Compiance on GMP inspection results. A memorandum with final recommendation
`will be entered in DARRTS after a final overall recommendation is made by the Office of
`Compliance regarding the cGMP status of all manufacturing facilities.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None at this time.
`
`11.
`
`Summary of CMC Assessments
`
`A.
`
`Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Substance
`Apixaban drug substance is a non-hygroscopic crystalline powder (melting point range of
`°C).
`(m4) has been identified during the polymorph screening. This
`form is consistently produced by the commercial process. Apixaban has demonstrated adequate
`stability to support a
`(mu) retest period and it is not sensitive to heat, light or moisture
`(when stored in
`(mm or other
`appropriate container). It is manufactured at the applicant's facility in Swords, Dublin, Ireland.
`The manufacturing site has an acceptable rating by the office of compliance.
`
`(b) (4)
`
`Apixaban is a non-ionizable compound, so its solubility is not affected by changes in pH. The
`average solubility of apixaban in aqueous media (from pH
`(m0) at 37°C i 3% is
`(m4)
`mg/mL. At the doses proposed in the application (2.5 and 5.0 mg) the dose to solubility ratio is
`(m4) of aqueous buffer over the above pH range. Using the Biophannaceutical
`Classification System 03CS), apixaban is classified as a BCS Class 111 drug (high solubility/low
`permeability).
`
`The commercial manufacturing process utilizes
`
`An appropriate control strategy and
`
`(b) (4)
`
`mu)
`
`CMC Review 01
`
`Reference ID: 3093460
`
`Page 7 of 33
`
`

`

`
`
`CMC REVIEW OF NDA 201532
`
`
`
`Executive Summary Section
`
`
`The dru substance is
`
`
`
`
`The drug substance is adequately characterized by elemental analysis, ultraviolet and visible
`absorption spectral analysis, infrared spectral analysis, nuclear magnetic resonance spectral
`analysis, mass spectral analysis and single crystal x—ray analysis. The molecule has no chiral
`centers.
`
`
`
`Batch analysis data includes 33 batches of drug substance produced by ldifi'erent processes (24
`of these by the commercial process and 8 at commercial scale). The batch analysis data confirms
`consistent quality by the commercial process.
`
`tel described and validated. The I-IPLC method for assa and
`
`Analytical methods are ade
`'
`urities was
`
`
`
`Adequate stability studies and forced defidation studies have beenperformedby the applicant.
`
`when stored as recommended. The drug
`The data supports a retest period of
`substance shows little if any degradatlon un er long term and accelerated storage conditions, and
`is not sensitive to light. Degradation does occur somewhat lmder stressed conditions; treatment
`with base, acid or peroxide for 14 days lead to hydrolysis related product albeit in limited
`
`amounts. On stability the drui substance was monitored for appearance, color, assay,
`
`and X—ray diffraction (no polymorphic changes have been
`
`impurities/degradants,
`detected in stability stu es .
`
`The applicant originally sought relief from— in the
`drug substance release specification, but at the Agency's request, they have included these in the
`release specification. Also the applicant did not want to report changes in operational parameters
`that were not critical quality attributes and handle them under their own quality management
`system, but at the Agency's request, they have agreed to report all changes in operational
`
`CMC Review 01
`
`Reference ID: 3093460
`
`Page 8 of 33
`
`

`

`Allin-n
`m.)
`
`CMC REVIEW OF NDA 201532
`
`Executive Summary Section
`
`“In."
`
`‘
`
`parameters outside the approved ranges as outlined in 21 CFR 314.70 even though they will be
`monitored by their own quality management system.
`
`Drug Product
`Eliquis® (apixaban tablets), 2.5 mg and 5.0 mg, is presented as an immediate release, film
`coated tablet to be distributed as a 60 or l80-count HDPE bottle with
`
`blister package; and a l4-count clear blister
`a lO—count clear
`
`
`"cation also describes and qualifies
`e 5.0 m h sician sam le .
`
`, but labels and labeling
`are not provided.
`
`The 2.5 mg tablet is yellow, round, biconvex and debossed “893” (bisect) “2 V2”. The 5.0 mg
`tablet is pink, oval, biconvex and debossed “894” (bisect) “5”. Formulation ingredients consist
`
`
`of active,
`(lactose and microc stalline cellulose)
`(croscarmellose sodium),
`
`sodium lauryl sulfate)
`ma
`esium stearate and
`film
`
`
`
`coatin . The coatin is shown to be
`
`
`
`
`No excipient is novel or of human origin.
`
`issues are adequately addressed for the lactose (sourced fiom-). Core and coating
`excipients are USP/NF/EP grade. Adequate specifications have been established for the
`excipients and film coating materials. Copies of certificates of analysis for the excipient lots
`used in the NDA registration batches are provided.
`
`Gh/[P inspections are pending for the proposed tablet manufacturing sites in the US. and Puerto
`Rico, and for the proposed contract packaging site in Italy.
`
`Commercial batch size is stated to be
`
`units for 2.50 tablets or
`
`
`
`Specifications for release and stability include testing for appearance, identity (Raman, IR,
`HPLC), assay (HPLC), related substances (HPLC), dosage uniformity (HPLC), disintegration
`(USP), dissolution (HPLC) and microbial limits (USP). Related susbstances include specified,
`
`CMC Review 01
`
`Reference ID: 3093460
`
`Page 9 of 33
`
`

`

`
`
`Executive Summary Section
`
`M“)
`unspecified and total impurities. Microbial limits testing is to be performed on
`batch. Descriptions of the analytical method are complete and provided in
`sufficient detail. Method validations, performed at the product development site, are complete
`and sufficient to support the intended use for each method.
`mm
`
`The proposed criteria are justified by ICH guidances, batch
`analysis data and stability study results, and appropriate developmental studies. A proposal to
`use
`mar Product
`
`release testing will include assay and content uniformity by HPLC and dissolution testing. A
`procedure and criterion for dissolution have been accepted. Reference standards used for the
`assay and related substances testing are those used for drug substance testing.
`
`Batch analysis data for each tablet strength is submitted for multiple clinical, developmental, and
`stability batches manufactured and packaged at the developmental site using the clinical fihn-
`coating. Data were also provided for process validation, stability and commercial batches
`manufactured and packaged at both proposed commercial sites using the commercial fihn—
`coating. All tablets manufactured since the phase 3 clinical studies used the same core
`formulations and manufacturing process. Batch sizes varied from
`mu) units. The
`analytical test results show consistency across manufacturing sites, tablet strengths, batch sizes,
`and tablet coating.
`
`The packaging presentations are multi-dose and unit dose container closure systems.
`Components for the multi—dose system are a (mu) white opaque HDPE bottle with
`A M‘ ) white opaque HDPE bottle($1311
`4 .
`.
`M” is desc