CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`201281Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`FDA CDER EES
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`
`DETAIL REPORT
`
`
`Acllon Goal:
`
`
`District Goal:
`
`
`
`
`
`
`01-DEC-2011
`
`
`
`Application:
`59
`‘ate:
`
`
`Reg-...¢ory:
`
`
`
`
`
`
`
`
`NDA 201281/000
`
`19-JAN-2011
`
`
`
`
`souAN-zmz
`
`
`
`AppIicant:
`
`
`
`BOEHRINGER PHARMS ,
`
`
`900 RIDGEBURY RD
`
`
`
`RIDGEFIELD. CT 06877
`
`
`
`
`
`
`
`Brand Name:
`
`
`Estab. Name:
`
`
`Generic Name:
`
`
`
`
`Linagliptin + Metformin Fixed Dose Combi
`
`
`
`
`
`
`‘ Linagliptin + Metformin Fixed Dose Combination
`
`
`
`
`
`Tablets
`
`
`
`
`
`
`WWW:
`
`Org. Code:
`
`
`
`
`4
`
`510
`
`Application Comment:
`
`
`
`
`Product Number; Dosage Form; Ingredient; Strengths
`
`
`
`
`
`001; TABLET; LINAGLIPTIN; 2.5MG
`
`
`
`
`001; TABLET; METFORMIN HYDROCHLORIDE; 500MG
`
`
`
`
`002; TABLET; LINAGLIPTIN; 2.5MG
`
`
`
`
`002; TABLET; METFORMIN HYDROCHLORIDE; 850MG
`
`
`
`
`
`003; TABLET; LINAGLIPTIN; 2,5MG
`
`
`
`
`003; TABLET; METFORMIN HYDROCHLORIDE; 1000MG
`
`
`
`
`PLEASE SEE BELOW FOR ESTABLISHMENT COMMENTS (on 21-JAN-2011 by K. SHARMA () )
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`FDA Contacts:
`
`
`
`
`
`
`K. SHARMA
`Project Manager
`
`
`S; TRAN
`Team Leader
`301 -796-1764
`
`
`
`
`
`
`
`
`Overall Recommendation:
`
`
`
`
`ACCEPTABLE
`
`
`
`WITHHOLD
`
`
`
`on 20-Dec-2011
`
`
`on 15-Nov-2011
`
`
`
`
`by D. SMITH
`
`
`by D. SMITH
`
`
`
`
`
`
`
`()
`
`()
`
`
`WlTHHOLD
`by EES_PROD
`on 22-AUG-2011
`
`
`
`
`
`
`
`January 25, 2012 2:37 PM
`
`
`
`
`
`
`
`FDA Confidential - Internal Distribution Only
`
`
`
`
`
`
`
`Page 1 at 10
`
`
`
`
`
`Reference ID: 3083109
`Reference ID: 3083109
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Establlshmont:
`
`CFN:
`
`(5N4)
`
`FEI:
`
`@(0
`
`(mo
`
`DMF No:
`
`Responsibilities:
`
`AADA:
`
`FINISHED DOSAGE RELEASE TESTER
`FINISHED DOSAGE STABILITY TESTER
`
`om n 3
`gmntshtmm
`Profile:
`
`ALTERNATE SITE 0F TESTING (RELEASE NAD STABILITY) FOR DRUG PRODUCT (on 21 -JAN-201 1 by K. SHARMA o )
`CONTROL TESTING LABORATORY
`OAI sums:
`NONE
`
`£13m“ ngletion mig‘on
`"films Name W Must T13
`”EM—— Reason
`SUBMITTED TO 00
`25dAN—201 1
`'
`
`greater
`
`SHARMAKH
`
`oc RECOMMENDATION
`
`mum-2011
`
`SUBMITTED Tooc
`
`02-DEC-2011
`
`oc RECOMMENDATION
`
`04-Dec-2011
`
`ACCEPTABLE
`BASED ON PROFILE
`
`INYARDA
`
`PATWARDHAN
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`
`
`January 25, 2012 2:37 PM
`
`FDA Confidential - lntarnal Distribution Only '
`
`Page 2 of 10
`
`Reference ID: 30831 09
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Establishment:
`
`CFN:
`
`FEI:
`
`”(9
`
`(5x4)
`
`DMF No:
`
`Responsibilities:
`
`AADA:
`
`FINISHED DOSAGE RELEASE TESTER
`FINISHED DOSAGE STABILITY TESTER
`
`Establishment
`Comment:
`Profile:
`
`ALTERNATE SITE FOR TESTING (RELEASE AND STABILITY FOR THE DRUG PRODUCT) (on 18-FEB-2011 by K. SHARMA
`0)
`OONTROL TESTING LABORATORY
`on Status: NONE
`
`
`Matti—Mi W mm mm ____Poeldon cmr
`
`Continent
`SUBMITTED To 0c
`18-FEB-2011
`
`SHARMAKH
`
`. mean
`
`SUBMITTED To DO
`
`22-FEB-2011
`
`Product Specific
`
`ASSIGNED INSPECTION To IB
`
`24-FEB‘2011
`
`Product Specific
`
`"M"
`INSPECTION PERFORMED
`Inspection of this contract control~testing facility was conducted as requested by FIFO-130 (DFFI).
`under FACTS assignment it 6757605. to cover the chemical testing activities related to Linagiptin/
`Mottormln HCI Tablets 2.5 mg l 500 mg. 2.5 mg / 850 mg, 2.5 mg I 1000 mg in connection with review
`of NDA # 201-281.
`
`This is the first time this contract testing facility is inspected by FDA. Current inspection disdomd no
`objectionable conditions and no FDA—483 was issued Two verbal observations were discussed with
`firm's management. The verbal observations were as lollows: persoan training procedures have no
`requirement for the anatysts‘ GMP training on a continued (yearly) basis. and sample intermediate-
`storage room not mappedstudied under conditions representative of rout'me sanple storage
`conditions.
`
`1 lirm‘s management oomrritted to provide continued GMP training to analysts and to quality the
`.pls storage area under loaded conditions.
`
`TOULOUSEM
`
`PHILPYE
`
`JOSECRuz
`
`INSPECTION SCHEDULED
`
`0X4)
`
`DO RECOMMENDATION
`
`19-SEP-2011
`
`OC RECOMMENDATION
`
`20689-2011
`
`SUBMITTED TO 00
`
`02-DEC-201 1
`
`0C RECOMMENDATION
`
`04-DEC-2011
`
`IFIIVERA
`
`STOCKM
`
`ACCEPTABLE
`INSPECTION
`
`INYARDA
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`PATWAFI DHAN
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`January 25, 2012 2:37 PM
`
`FDA Confidential - Inter-ml Distribution Only
`
`Page 3 of 10
`
`Reference ID: 30831 09
`
`

`

`FDA CDER EES
`ESTABUSHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Establishment:
`
`FEI: 3002806556
`CFN: 9610492
`BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG
`
`DMF No:
`
`Responsiblllllos:
`
`BINGER STREET 173
`INGEHEIM AM RHEIN, . GERMANY
`
`AADA:
`
`DRUG SUBSTANCE LABELER
`DRUG SUBSTANCE MANUFACTURER
`
`DRUG SUBSTANCE PACKAGER
`
`DRUG SUBSTANCE STABILITY TESTER
`
`FINISHED DOSAGE LABELER
`
`FINISHED DOSAGE MANUFACTURER
`
`FINISHED DOSAGE PACKAGER
`
`FINISHED DOSAGE RELEASE TESTER
`
`FINISHED DOSAGE STABILITY TESTER
`
`Establishmt
`Comment:
`
`Profile:
`
`IN ADDITION. ALSO RESPONSIBLE FOR TESTING OF EXCIPIENTS AND METFORMIN (on 02-DEc-2011 by 5.
`PATWARDHAN (HF-01) 301-796-4085)
`ALL ASPECTS OF MANUFACTURING. PACKAGING, LABELING AND TESTING (RELEASE AND STABILITY) FOR DRUG
`PRODUCT (on mam-2011 by K. SHARMA o )
`0(4) PACKAGING. LABELING, QUALITY CONTROL OPERATIONS,
`ALL ASPECTS OF THE MANUFACTURING
`AND STABILITY TESTING FOR DRUG SUBSTANCE LINAGLIPTIN (on 21 JAN—2011 by K. SHARMA () )
`NON-STERILE API BY CHEMICAL SYNTHESIS
`OAI Status: NONE
`
`TABLETS. PROMPT RELEASE
`
`NONE
`
`“13mm Name
`Comm
`SlBMlTTED TO 00
`
`mum Rams! Tm Planned Compjetig Decision
`_ R
`
`25~JAN~201 1
`
`Creator
`
`SHARMAKH
`
`0
`
`OMMENDATION
`
`26-JAN-201 1
`
`.
`
`ACCEPTABLE
`BASED ON PROFILE
`
`INYARDA
`
`SUBMITTED TO GO
`
`02-DEC-201 1
`
`OC RECOMMENDATION
`
`04-Dec-2011
`
`SUBMITTED T0 00
`
`254AN-201 1
`
`SUBMITTED TO DO
`
`KHAN-2011
`
`10-Day Letter
`
`DO RECOMMENDATION
`
`31 «IAN-2011
`
`‘
`
`00 RECOMMENDATION
`
`02-FEB-201 I
`
`SUBMITTED TO 06
`
`02-DEC-2011
`
`SUBMITTED TO DO
`
`04-DEC-2011
`
`10—Day Letter
`
`DO RECOMMENDATION
`
`20-DEC-2011
`
`PATWARDHAN
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`SHARMAKH
`
`INYARDA
`
`PHILPYE
`ACCEPTABLE
`BASED ON FILE REVIEW
`
`SMITHDE
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`PATWARDHAN
`
`STOCKM
`
`PHILPYE
`ACCEPTABLE
`BASED ON FILE REVIEW
`
`January 25, 2012 2:37 PM
`
`FDA Confidential - Internal Distribution Only
`
`Page 4 o! 10
`
`Reference ID: 30831 09
`
`

`

`FDA- CDER EES
`
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`
`DETAIL REPORT
`
`
`
`
`
`OL
`
`
`OMMENDATION
`
`
`
`20-DEC-2011
`
`
`
`
`SMITHDE
`ACCEPTABLE
`
`
`
`DISTRICT RECOMMENDATION
`
`
`
`
`January 25, 2012 2:37 PM
`
`
`
`
`
`
`FDA Confidential - Internal Distribution Only
`
`
`
`
`
`
`
`Page 5 of 10
`
`
`
`
`
`
`Reference ID: 3083109
`Reference ID: 3083109
`
`

`

`FDA CDER EES
`
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`
`DETAIL REPORT
`
`
`FEI: 1510690
`CFN: 1510690
`
`
`
`BOEHRINGER INGELHEIM ROXANE INCORPORATED
`
`
`
`1809 WILSON RD
`
`
`
`COLUMBUS. OH 432289579
`
`
`
`
`
`AADA:
`
`
`
`
`
`
`
`
`
`FINISHED DOSAGE LABELER
`
`
`
`FINISHED DOSAGE PACKAGER
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ALTERNATE PACKAGING AND LABELING FOR THE DRUG PRODUCT (on 13-APR-2011 by K. SHARMA () )
`TABLETS, PROMPT RELEASE
`OAI Status:
`NONE
`
`
`
`
`
`
`
`
`
`Establishment:
`
`
`
`DMF No:
`
`
`Responsibilities:
`
`
`
`
`
`ommen :
`Establishtment
`
`Profile:
`
`
`Planned Comnletion Decision
`Rgguest Tyge
`Milestone Date
`Milestone Name
`
`
`
`
`
`
`
`
`
`Comment
`Reason
`
`SUBMITTED TO 00
`25-JAN-2011
`
`
`
`
`
`
`
`
`
`
`
`
`
`' Creator
`
`
`
`SHARMAKH
`
`REQUEST CANCELLED
`
`
`
`
`26-JAN-2011
`
`
`
`SUBMITTED TO OC
`
`
`
`
`
`13-APR-201 1
`
`OC RECOMMENDATION
`
`
`
`
`13-APR-2011
`
`SUBMITTED TO 00
`
`
`
`
`
`OC RECOMMENDATION
`
`
`
`
`02-DEC-2011
`
`04-DEC-2011
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`SHARMAKH
`IRRELEVANT FACILITY/PROFILE
`
`
`
`
`SHARMAKH
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`
`
`
`
`TOULQUSEM
`
`
`
`PATWARDHAN
`
`
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`
`
`
`
`STOCKM
`
`
`
`January 25, 2012 2:37 PM
`
`
`
`
`
`
`
`FDA Confidential - Internal Distribution Only
`
`
`
`
`
`
`Page 6 of 10
`
`
`
`
`
`
`Reference ID: 3083109
`Reference ID: 3083109
`
`

`

`Establishment
`
`CFN:
`
`FDA CDER EES
`.
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`0x4)
`
`FEI:
`
`(m4)
`
`AADA:
`
`FINISHED DOSAGE RELEASE TESTER
`FINISHED DOSAGE STABILITY TESTER
`
`ALSO RESPONSIBLE FOR TESTING OF EXCIPIENTS (on 02-DEC-2011 by S. PATWARDHAN (HF—01) 301-796-4085)
`DRUG PRODUCT RELEASE AND STABILITY TESTER (on 13-APR-201 1 by K. SHARMA () )
`CONTROL TESTING LABORATORY
`OAI Status:
`NONE
`
`DMF No:
`
`Responsibilities:
`
`onlnen 2
`Establishfnm
`
`Profile:
`
`353319;)
`Planned Commetlon
`mm Mm W Muss! TIE
`20m___—_____ Reason
`SUBMTrrED To OC
`2NAN-2011
`
`Cagn-
`
`SHARMAKH
`
`REQUEST CANCELLED
`
`26-JAN-201 1
`
`SUBMITTED TO OC
`
`13-APR-2011
`
`OC RECOMMENDATION
`
`13-APR-2011
`
`SUBMITTED TO 00
`
`OZ—DEC-ZOH
`
`oc RECOMMENDATION
`
`04-DEc-2011
`
`SHARMAKH
`IRRELEVANT FACILITVIPROFILE
`
`ACCEPTABLE
`BASED ON PROFILE
`
`SHARMAKH
`
`TOULOUSEM
`
`PATWARDHAN
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`
`
`January 25. 2012 2:37 PM
`
`FDA ConfldentIaI - Internal Distrlmtion am
`
`Page 7 of 10
`
`Reference ID: 30831 09
`
`

`

`Establishment:
`
`CFN:
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`(hm
`
`FE:
`om
`
`DMF No:
`
`AADA;
`
`memlizm:
`
`DFIUG SUBSTANCE RELEASE TESTER
`
`aigflblishmm
`Profile:
`
`STABILITY TESTING FOR DRUG SUBSTANCE METFORMIN HYDROCHLORIDE (on 21UAN-2on by KL SHARMA 0)
`CONTROL TESTING LABORATORY
`CAI sums: NONE
`
`
`L—MiN-me W W W man—.— 0'9”"
`
`mmmnt
`SUBMITTED To oc
`
`25-JAN-2on
`
`SHARMAKH
`
`SUBMITTED TO DO
`NEW FIRM
`
`26-JAN-201 1
`
`Product Specific
`
`ASSIGNED INSPECTION TO IB
`
`31-JAN-2011
`
`PmSpeciflc
`
`INSPECTION SCHEDULED
`
`UNDER REVIEW
`
`21-SEP—2011
`
`DO RECOMMENDATION
`
`07-Nov-2011
`
`oc RECOMMENDATION
`
`15-Nov-2011
`
`SI "‘- "'I'I'ED To 00
`
`O2-DEC-201 1
`
`oc. . .cCOMMENDATION
`
`04-DEC-2011
`
`INYARDA
`
`PHILPYE
`
`IRIVERA
`
`STOCKM
`
`STOCKM
`
`(m4)
`
`ACCEPTABLE
`INSPECTION
`
`SMITHDE
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`PATWARDHAN
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`
`
`January 25, 2012 2:37 PM
`
`FDA Confidential - Internal Distrlbuuon Only
`
`Page 8 of 10
`
`Reference ID: 30831 09
`
`

`

`Establishment:
`
`CFN:
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`OX4)
`
`(5M4)
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE STABILITY TESTER
`
`Emblislamem
`Profile:
`
`STABILITY TESTING FOR DRUG SUBSTANCE METFORMIN HYDROCHLORIDE (on 25UAN-2011 by K. SHARMA o )
`CONTROL TESTING LABORATORY
`DAI Status: NONE
`
`Milestom Name W m Plnnmg nggletign Docislgn
`
`Comment
`Ron D
`SUBMITTED TO OC
`25UAN—201 I
`
`SUBMR'rED TO DO
`NEW FIRM
`
`mum-2011
`
`Product Specific
`
`'
`
`ASSIGNED INSPECTION T0 IB
`
`31-JAN-2011
`
`Product Specific
`
`INSPECTION SCHEDULED
`
`INSPECTION PERFORMED
`
`(m4)
`
`0x4)
`
`UNDER REVIEW
`
`21-SEP-2011
`
`DO RECOMMENDATION
`
`0&NOV-2011
`
`oc RECOMMENDATTON
`
`07-Nov—2011
`
`sup....1'IED To OC
`
`02—DEC«2011
`
`oc RECOMMENDATION
`
`04-DEC-2011
`
`Crmor
`
`SHARMAKH
`
`INYARDA
`
`PHILPYE
`
`IRIVERA
`
`DEMERSON
`
`STOCKM
`
`STOCKM
`
`0x4)
`
`(5x4)
`
`ACCEPTABLE
`INSPECTION
`
`INYARDA
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`PATWARDHAN
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`
`
`January 25, 2012 2:37 PM
`
`FDA Confidential ~ Internal Disiribution Only
`
`Page 9 of 10
`
`Reference ID: 30831 09
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Establishment:
`
`CFN:
`
`FEI:
`
`(51(4)
`
`«9(4)
`
`DMF No:
`
`Responslblllties:
`
`AADA:
`
`DRUG SUBSTANCE LABELER
`DRUG SUBSTANCE MANUFACTURER
`
`DRUG. SUBSTANCE PACKAGER
`
`Establishment
`Comment
`Profile:
`
`MANUFACTURING. PACKAGING AND LABEUNG FOR DRUG SUBSTANCE (METFORMIN HYDROCHLORIDE) (on 21-JAN-
`zott by K. SHARMA 0)
`NON-STERILE API BY CHEMICAL SYNTHESIS
`CAI Status: NONE
`
`
`Was...— MLIEJSLILDBE. w W m__ Cream
`W—__—_— Reason
`SUBMITTED TO OC
`25-JAN-201 1
`
`SHARMAKH
`
`SUBMITTED TO Do
`NEw FIRM
`
`26-JAN-2011
`
`Product Specific
`
`ASSIGNED INSPECTION To IB
`
`sum-2011
`
`Product Specific
`
`INSPECTION SCHEDULED
`
`UNDER REVIEW
`
`21-SEP-2011
`
`DO RECOMMENDATION
`
`24~OCT~2011
`
`oc RECOMMENDATION
`
`24-0CT-2011
`
`SUBMITTED TO DO
`
`02-DEC-2011
`
`oc RECOMMENDATION
`
`04-Dec-2011
`
`INYARDA
`
`PHILPYE
`
`IRIVERA
`
`STOCKM
`
`STOCKM
`
`(m4)
`
`ACCEPTABLE
`INSPECTION
`
`STOCKM
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`PATWARDHAN
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`January 25. 2012 2.37 PM
`
`FDA Confidential - InternaI Distribution Only
`
`Page 10 of 10
`
`Reference ID: 30831 09
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`NIKOO N MANOCHEHRI KALANTARI
`02/06/2012
`
`Reference ID: 3083109
`
`

`

` Memorandum to NDA 201,281 File
`
`From: Sheldon Markofsky (Chemistry Reviewer)
`Date: December 22, 2011
`
`Subject:
`Office of Manufacturing & Product Quality Acceptable
`Recommendation for the Facilities of NDA 201,281
`
`The Office of Manufacturing & Product Quality (OMPQ) has
`determined that the relevant facilities employed for the manufacture
`and testing of the drug substances and the drug product (Linagliptin
`and Metformin Hydrochloride Tablets) are Acceptable. Therefore,
`from both a Chemistry and OMPQ point of view, this NDA (201281)
`can be approved
`
`Reference ID: 3062747
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`SHELDON B MARKOFSKY
`12/22/2011
`
`ALI H AL HAKIM
`12/22/2011
`
`Reference ID: 3062747
`
`

`

` Memorandum to NDA 201,281 File
`
`From: Sheldon Markofsky (Chemistry Reviewer)
`Date: November 8, 2011
`
`Subject:
`Office of Compliance “Withhold” Recommendation for NDA 201,281
`
`The office of Compliance has recommended a “Withhold” for the
`approval of the
` which is used for testing
`metformin HCl and the excipients that are employed for the Drug
`Product (Linagliptin and Metformin HCl Tablets). The Office of
`Manufacturing and Product Quality (OMPQ} stated that the “withhold”
`recommendation will not change prior to the PDUFA goal date for
`NDA 201,281.
`
`Reference ID: 3041192
`
`(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/
`----------------------------------------------------
`SHELDON B MARKOFSKY
`11/08/2011
`Compliance 'Withhold" recommendation Memo
`
`ALI H AL HAKIM
`11/08/2011
`CMC recommendation is CR due to the Withold Recommednation issued by office of compliance.
`
`Reference ID: 3041192
`
`

`

`
`
`NDA 201-281
`
`Trade*
`
`(Linagliptin and Metformin hydrochloride) Tablets
`‘ Boehringer lngelheim has not yet finalized (selected) a trade name.
`
`Boehringer lngelheim Pharmaceuticals, Inc
`
`Sheldon Markofsky, Ph.D.
`
`Division of Metabolism and Endocrine Products (HFD-510)
`
`and
`
`Office of New Drug Quality Assessment Ill
`Branch VII
`
`File: n201281Rev2a
`
`Reference ID: 3020161
`
`

`

`FF!“
`“gag
`
`CHEMISTRY REVIEW
`
`FRED
`,
`t
`I
`
`Table of Contents
`
`Table of Contents ....................................................................................... 2
`
`Chemistry Review Data Sheet................................................................... 3
`
`The Executive Summary............................................................................ 8
`
`I.
`
`Recommendations ................................................................................................ 8
`
`A.
`
`B.
`
`Recommendation and Conclusion on Approvability ...................................................... 8
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements. and/or
`Risk Management Steps, if Approvable ........................................................................ 8
`
`II.
`
`Summary of Chemistry Assessments ................................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) .............................................. 8
`
`B. Description of How the Drug Product is Intended to be Used ......................................... 10
`
`C. Basis for Approvability or Not-Approval Recommendation .............................................. 11
`
`Ill. Administrative .......................................................................................................... 11
`
`A. Reviewer's Signature ....................................................................................................... 11
`B. Endorsement Block.......................................................................................................... 11
`
`C. CC Block.......................................................................................................................... 11
`
`Chemistry Assessment .................................................Starting on pp. 12
`
`I
`
`S
`
`P
`
`A
`R
`
`DRUG SUBSTANCES ......................................................................................... pp. 12
`
`DRUG PRODUCT ............................................................................................... pp. 12
`
`APPENDICES (Attachments) ..................................................................................... 27
`REGIONAL INFORMATION ....................................................................................... 27
`
`ll.
`
`List Of Deficiencies To Be Communicated ......................................................... 30
`
`2
`
`Reference ID: 30201 61
`
`

`

`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`3
`
`1. NDA 201-281
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: 23-Sept-2011
`
`4. REVIEWER: Sheldon Markofsky, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`Previous Documents
`NDA (Original)
`Initial Quality/ CMC Assessment
`Amendmenta
`Amendmentb
`Chemistry Review # 1
`Information Request Letter
`
`Document Date
`19-Jan-2011
`01-March-2011
`12-April-2011
`27-April-2011
`06-June-2011
`06-June-2011
`
`a) The 4-12-11 amendment provided up-dated container/closure and manufacturing and testing
` facility information.
`b) The 4-27-11 amendment provided up-dated information on in-use stability studies.
`
`6. SUBMISSION(S) BEING REVIEWED:
`Document Date
`Submission(s) Reviewed
`Amendmenta
`01-July-2011
`Amendmentb
`26-Aug-2011
`a) The 7-1-11 amendment provides responses to our IR letter of 6-6-2011.
`b) The 8-26 amendment updated the specifications for the container/closure systems.
`
`7. NAM.E & ADDRESS OF APPLICANT:
`
`Address:
`
`Name: Boehringer Ingelheim Pharmaceuticals, Inc.
`900 Ridgebury Road
`PO Box 368
`Ridgefield, CT 06877-0368
`Representative: Dawn Collette, Associate Director, DRA
`Telephone: 203-798-4268
`
`Reference ID: 3020161
`
`

`

`4
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Not yet determined
`b) Non-Proprietary Name: Linagliptin and Metformin Hydrochloride Tablets
`c) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type:1
`• Submission Priority: S
` 9. LEGAL BASIS FOR SUBMISSION: 505(b)(2)
`
`(The reference listed drug is Glucophage (metformin HCl tablets)
`
`10. PHARMACOL. CATEGORY: Treatment of type 2 diabetes mellitus
`
`11. DOSAGE FORM: Tablets
`
`12. STRENGTH/POTENCY:
`2.5/500, 2.5/850, 2.5/1000 mg (linagliptin/metformin HCl)
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED: X Rx ___OT
`
` 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:
`
`Linagliptin
`
`C25H28N8O2
`472.54 g/mol.
`
`Reference ID: 3020161
`
`

`

`5
`
`INN: Linagliptin
`USAN: Linagliptin
`
`Chemical names:
`
`(Chemical Abstracts)
`1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7- (2-butyn-1-yl)-3,7-dihydro-
`3 methyl-1-[(4-methyl-2- quinazolinyl)methyl]-
`
`(IUPAC) and (INN)
`8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-yn-1-yl-3-methyl-1- [(4-methylquinazolin-2
`yl)methyl]-3,7-dihydro-1H-purine- 2,6-dione
`
`CAS Registry Number 668270-12-0
`Company Code Number BI 1356 BS
`
`Metformin HCl
`
`C4H11N5 • HCl
`165.62 g/mol
`
`Chemical names:
`
`Metformin Hydrochloride (INN and USAN names)
`
`N,N-Dimethylimidodicarbonimidic diamide hydrochloride
`
`N,N-Dimethylbiguanide hydrochloride
`
`CAS Registry Number: 115-70-4
`
`Reference ID: 3020161
`
`

`

`6
`
`Deleted: ¶
`
`COMMENTS
`
`Reviewed by
`S. Markofsky
`
`&H
`
`.Khorshidi
`Reviewed by
`Don Klein
`
`Adequate
`
`3-24-10
`
`Reviewed by R.
`Agarwal
`
`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)
`
`B. Other Documents:
`
`DOCUMENT
`
`PIND
`
`APPLICATION NUMBER
`105,055
`
`DESCRIPTION
`PIND for Linagliptin/metformin
`HCl tablets
`
`Reference ID: 3020161
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DMF
`#
`
`TYPE HOLDER
`
`ITEM
`REFERENCED
`
`CODE
`1
`
`STATUS2
`
`DATE
`REVIEW
`COMPLETED
`2-1-08
`
`Adequate
`
`3-10-10
`
`Adequate
`
`9-15-00
`
`II
`
`III
`
`III
`
`Chemistry Review Data Sheet
`
`3
`
`3
`
`3
`
`(b) (4)
`
`(b) (4)
`
`

`

`7
`
`18. STATUS:
`
`RECOMMENDATION
`
`ONDC:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`WITHHOLD
`EES
`Pending
`Pharm/Tox
`Methods Validation Acceptable
`EA
`Acceptable
`Microbiology
`N/A
`ONDQA Dissolution
`Acceptable
`Review
`
`DATE
`
`REVIEWER
`
`8-22-11
`
`6-6-11
`6-6-11
`
`9-19-11
`
`
`David Carlson
`S. B. Markofsky
`S. B. Markofsky
`
`Houda Mahayni
`
`19. ORDER OF REVIEW: N/A (OGD Only)
`
`Reference ID: 3020161
`
`

`

`
`
`8
`
`
`
`
`
`The Executive Summary
`The Chemistry Review for NDA 201-281
` I.
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From a Chemistry, Manufacturing, and Controls (CMC) point of
`view, this NDA can be approved.
`
`However, the Establishment Inspection work for the relevant
`manufacturing and testing facilities has not been completed: and
`one testing site has been given a WITHHOLD finding. Thus, the
`CMC recommendation for approval does not reflect any facility
`inspection issues.
`
`Recommendation on Phase 4 (Post-Marketing)
`B.
`Commitments, Agreements, and/or Risk Management Steps, if
`Approvable
`None
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product and Drug Substances
`
`1) Drug Product
`The drug product, whose trade name has not yet been determined, consists of
`linagliptin / metformin hydrochloride immediate–release (film-coated) tablets.
`The combination of linagliptin, a dipeptidyl peptidase-4 inhibitor used to improve
`glycemic control, and metformin hydrochloride, an antihyperglycemic agent, is
`indicated as an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes when treatment with both linagliptin and metformin are
`appropriate. Linagliptin / metformin hydrochloride tablets are supplied in 2.5
`mg/500 mg, 2.5 mg/850 mg, and 2.5 mg/1000 mg strengths. The tablets of
`various strengths are oval, debossed on one side with the Boehringer Ingelheim
`company symbol, and on the other side with a symbol appropriate to its strength.
`The tablets are distinguished by a characteristic color as shown below.
`Strength
`Strength debossment symbol Color
`Oval Size
`2.5 mg/500 mg, D2/500
`Light yellow 16 mm long
`2.5 mg/850 mg, D2/850
`Light orange 19 mm long
`
`Deleted: ¶
`Formatted: Indent: Left: 0"
`Formatted: Heading 3, Indent: Left:
` -0.06", Hanging: 0.06"
`Deleted: ¶
`
`Reference ID: 3020161
`
`

`

`|2.5 mg/1000 mg,
`
`02/1000
`
`Light pink
`
`21 mm long
`
`I
`
`The tablets are packaged in high density polyethylene (HDPE) bottles containing
`a desiccant and closed with plastic screw closures as summarized in the
`following table.
`
`Bottle type
`
`no. of film coated
`tablets
`
`Bottle size
`
`Intended use
`
`60 ml
`
`physician samples only
`
`150 ml
`
`one month‘ supply
`
`three months” supply
`
`for mail order pharmacies
`
`
`
`
`Ill-count:
`(0(4)
`
`induction foil seal
`
`60-count:
`0-)“)
`induction foil seal
`
`ISO-count:
`0-)“)
`induction foil seal
`
`2000-coru1l;
`standard closure
`
`14
`
`60
`
`18
`
`Adequate drug product specifications were provided for the Description of the
`dosage form, Identification of the active ingredients,
`(”"9 and
`Uniformity of Dosage Units, Assay, Dissolution. and Degradation Products for
`both drug substances.
`.
`
`Besides linagliptin and metformin HCL, the drug product contains the following
`inactive ingredients: arginine. corn starch, copovidone, colloidal silicon
`dioxide, magnesium stearate, titanium dioxide, propylene glycol, hypromellose,
`talc, yellow ferric oxide (2.5 mg/500 mg; 2.5 mg/850 mg tablets) and/or red ferric
`oxide (2.5 mg/850 mg; 2.5 mg/1000 mg tablets). All of the inactive ingredients
`are compendial.
`
`2) Drug Substances
`
`Linagliptin
`
`Linagliptin is manufactured by Boehringer lngelheim Pharma GmbH & Co. KG in
`Germany. The firm (Bl) referenced their approved NDA 201-280, (Linagliptin
`Tablets) for the CMC information related to the linagliptin drug substance. This
`information is captured in Chemistry Reviews 1 and 2 of NDA 201-280.
`Linagliptin is a
`00(4) white to yellowish solid,
`
`00(4)
`
`Reference ID: 3020161
`
`

`

`10
`
`9"" Boehringer lngelheim classifies this drug substance as a Class III
`compound according to the Biopharmaceutical Classification System (BCS)
`because of its high solubility and low bioavailability. In this connection, linagliptin
`shows high BCS defined solubility (> 1 mg/ml) in aqueous media up to pH 8.
`Satisfactory stability data was provided to support a retest date of 8months for
`the drug substance for storage at 25°C/60 % R.H. Based on the Chemistry
`reviews of Boehringer lngelheim's approved NDA 201-280 (Linagliptin Tablets),
`this drug substance (linagliptin) is adequate to support this NDA (201-281).
`
`Metformin HCL
`
`“"0. Bl
`Metformin hydrochloride (USP) is manufactured by
`referenced DMF W" for the CMC information related to the metfonnin HCI
`
`drug substance, and based on the Chemistry reviews of this DMF, this drug
`substance (metfonnin HCI) is adequate to support this NDA (201-281).
`
`Boehringer lngelheim‘s specification and testing procedures also comply with the
`USP monograph for metformin HCI. In addition, tests are performed on certain
`cm to comply with the
`(m4) for this drug substance.
`
`suppliers specification, described in DMF
`
`B. Description of How the Drug Product is Intended to be Used
`
`The individualized starting dose of the linagliptin / metformin hydrochloride tablets
`should be based on the patient's current regimen and be given twice daily with
`meals, with gradual dose escalation, as appropriate. The maximum
`recommended dose is 2.5 mg linagliptin/1000 mg metfonnin hydrochloride twice
`daily. The stability studies support an expiration-dating period of 24 months for all
`strengths of the tablets when stored at room temperature [25°C (77°F)], with
`excursions permitted between 59 °F to 86°F (15°C to 30°C) packaged in all of
`the proposed commercial container closure systems. Consequently, a 24 month
`expiry is granted.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`Reference ID: 30201 61
`
`

`

`11
`
`From a Chemistry, Manufacturing, and Controls (CMC) point of view, this NDA
`can be approved, on the following basis:
`
`• Adequate information was provided in the NDA for the synthesis,
`purification and controls of the drug substances
`
`• Adequate manufacturing information to support the proposed to-be-
`marketed drug product
`
`• Adequate specifications and controls for the drug product
`
`• Satisfactory methods to support lot release and stability monitoring of the
`drug product
`
`• Adequate stability package to support the recommended expiry period of
`the drug product
`
`However, the Establishment Inspection work for the relevant manufacturing and
`testing facilities has not been completed: and one testing site has been given a
`WITHHOLD finding. Thus, the CMC recommendation for approval does not
`reflect any facility inspection issues.
`
` [Labeling will be finalized at a later date as part of the review team's labeling negotiation.]
`
`III. Administrative
`
`A. Reviewer’s Signatures
`
``
`
`Sheldon Markofsky, Ph.D. (Chemistry Reviewer)
`
`B. Endorsement Block (OGD only)
`
`
`N/A
`
`C. CC Block (OGD only)
`N/A
`
`Reference ID: 3020161
`
`(b) (4)
`
`19 pages has been withheld in full as B(4) CCI/TS immediately
`following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`SHELDON B MARKOFSKY
`09/26/2011
`
`ALI H AL HAKIM
`09/26/2011
`
`Reference ID: 3020161
`
`

`

`CHEMISTRY REVIEW
`
`NBA 201 -281
`
`Trade*
`
`(Linagliptin and Metformin hydrochloride) Tablets
`* Boehringer lngelheim has not yet finalized (selected) a trade name.
`
`Boehringer lngelheim Pharmaceuticals, Inc
`
`Sheldon Markofsky, Ph.D.
`
`Division of Metabolism and Endocrine Products (HFD-510)
`
`and
`
`Office of New Drug Quality Assessment Ill
`Branch VII
`
`Reference ID: 2961261
`
`

`

` w
`CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents ....................................................................................... 2
`
`Chemistry Review Data Sheet ................................................................... 3
`
`The Executive Summary............................................................................ 8
`
`I.
`
`Recommendations ................................................................................................ 8
`
`A.
`
`B.
`
`Recommendation and Conclusion on Approvability ...................................................... 8
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable ........................................................................ 8
`
`II.
`
`Summary of Chemistry Assessments ................................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) .............................................. 8
`
`B. Description of How the Drug Product is Intended to be Used ......................................... 10
`
`C. Basis for Approvability or Not-Approval Recommendation .............................................. 10
`
`Ill. Administrative .......................................................................................................... 11
`
`A. Reviewer's Signature ....................................................................................................... 11
`
`B. Endorsement Block .......................................................................................................... 11
`
`C. CC Block.......................................................................................................................... 11
`
`Chemistry Assessment ................................................. Starting on pp. 12
`
`|
`
`S
`
`P
`
`A
`
`R
`
`DRUG SUBSTANCE ............................................................................................ pp. 12
`
`DRUG PRODUCT ............................................................................................... pp. 27
`
`APPENDICES (Attachments) ................................................................................... 136
`
`REGIONAL INFORMATION ..................................................................................... N/A
`
`II.
`
`List Of Deficiencies To Be Communicated ....................................................... 139
`
`Reference ID: 2961261
`
`2
`
`

`

`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`3
`
`
`1. NDA 201-281
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 13–June-2011
`
`4. REVIEWER: Sheldon Markofsky, Ph.D.
`
`
`5. PREVIOUS DOCUMENTS:
`Previous Documents
`NDA (Original)
`Initial Quality/ CMC Assessment
`
`Document Date
`19-Jan-2011
`01-March-2011
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`Document Date
`Submission(s) Reviewed
`19-Jan-2011
`NDA Original
`Amendmenta
`12-April-2011
`Amendmentb
`27-April-2011
`a) The 4-12-11 amendment provides up-dated container/closure and manufacturing and testing
`facility information.
`b) The 4-27-11 amendment provides up-dated information on in-use stability studies.
`
`7. NAM.E & ADDRESS OF APPLICANT:
`
`
`Address:
`
`Name: Boehringer Ingelheim Pharmaceuticals, Inc.
`900 Ridgebury Road
`PO Box 368
`Ridge