CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202270Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`FDA CDER EE-S
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`NDA 2022701000
`
`23-SEP-2010
`
`O3-FEB-2012
`
`MERCK SHARP DOHME
`
`
`UGZCD 48
`
`'
`
`
`Action Goal:
`mom: Goal:
`
`
`Brand Name:
`
`hub. Nam:
`
`24-MAv-2o11
`
`Sitainptin + Metformin Extended Release
`
`
`
`
`NORTH WALES, PA 19454
`
`
`
`
`
`
`3
`
`51°
`
`
`
`
`
`
`We Name:
`
`
`
`
`
`
`
`
`3’
`
`Anne-Hon:
`
`a Duo:
`k ‘ .Atory:
`
`Applicant:
`
`Monty:
`.
`.
`0" cm‘
`
`Application Comm:
`
`
`
`FDA Com:
`
`
`
`Product Number; Dosage Form; Ingredient; 3mm
`
`001; TABLET; SITAGLIPTIN; SOMG
`001; TABLET; METFORMIN HYDROCHLORIDE; SOOMG
`
`
`
`
`002; TABLET; SITAGLIPTIN; 50MG
`
`
`
`002; TABLET; METFORMIN HYDROCHLORIDE; 1000MG
`
`
`
`
`SEE ESTABLISHMENT COMMENTS FOR THIS NEw NOA (on 01~OCT~2010 by K. SHARMA () )
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Project Manager
`Team Leader
`
`
`
`K. SHARMA
`
`3. TRAN
`
`
`301-796-1764
`
`(HFD-320)
`
`301-796-3203
`
`OVOI'OII Emulation:
`
`ACCEPTABLE
`
`PENDING
`
`WITHHOLD
`
`WITHHOLD
`
`WITHHOLD
`
`PENDING
`
`PENDING
`
`PENDING
`
`PENDING
`
`PENDING
`
`WITHHOLD
`
`WITHHOLD
`
`on 25-JAN-2012
`
`
`by _S. HERTZ
`
`on 05-JAN-2012
`
`
`by EES_PROD
`
`on OMAN-2012
`
`
`by EES_PROD
`
`on 04-DEC-2011
`
`
`by EES_PROD
`
`on 10~AUG-2011
`
`
`by EES_PROD
`
`on 04-AUG-2011
`
`
`by EES_PROD
`
`on 04-AUG-2011
`
`
`by EES_PROD
`
`on 04-AU62011
`
`
`by EES_PROD
`
`on 04-AUG-2011
`
`
`by EES_PROD
`
`on 03-AUG-2011
`
`
`by EES_PROD
`
`on 03-AUG2011
`
`
`by EES_PROD
`
`on 21-JUL-2011
`
`
`by EES_PROD
`
`by EES_PROD
`WITHHOLD
`on 25-MAY-2011
`
`W
`
`January 20, 2012 1:30 PM
`
`
`
`
`
`
`
`WA Confidential . Inland momma" Only
`
`Pagflof!
`
`Reference ID: 3083898
`Reference ID: 3083898
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`(W)
`
`am
`
`am
`
`MBA:
`
`Est-mm:
`
`cm:
`
`(mo
`
`on: No:
`
`WW DRUG SUBSTANCE MANUFACTURER
`
`DRUG SUBSTANCE PACKAGER
`
`DRUG SUBSTANCE RELEASE TESTER
`
`DRUG SUBSTANCE STABILITY TESTER
`
`WM DRUG SUBSTANCE (srTAGLIPTIN PHOSPHATE) MANUFACTURING. PACKAGING, AND RELEASEISTABILITY TESTING (on
`CW
`01-OCT-2010 by K. SHARMA () )
`man:
`NDN-STERILE API BY CHEMICAL SYNTHESIS
`
`on am: NONE
`
`MWWWMM—
`92mm” HARMAKH
`SUBMITTED TO GO
`05-OCT-2010
`
`OC RECOMMENDATION
`
`05-OCT-2010
`
`ACCEPTABLE
`BASED ON PROFIIE
`
`STOCKM
`
`SUBMITTED TO 00
`
`04-AUG-2011
`
`SHARMAKH
`
`OC RECOMMENDATION
`
`04-AUG-201 1
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`mauuuum
`
`FDACummd-mmmm
`
`93902019
`
`Reference ID: 3083898
`
`

`

`Establishment:
`
`CFN:
`
`(6) (4)
`
`(b) (4)
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`(4)
`
`PEI:
`
`0’)
`
`FDA CDER EES
`
`DUI No:
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE MANUFACTURER
`
`DRUG SUBSTANCE RELEASE TESTER
`
`DRUG SUBSTANCE STABILITY TESTER
`
`WM
`Comm:
`Profile:
`
`DRUG SUBSTANCE (METFORMIN HYDROCHLORIDE) MANUFACTURING. TESTING AND RELEASE (on o1-oc1t2010 by K,
`SHARMA 0)
`NON-STERILE API BY CHEMICAL SYNTHESIS
`OAI 3mm NONE
`
`Wm.— 312mm. mm W Baum—— W—
`b
`SUBMITTED TO 06
`05—OCT-201 0
`
`§HARMAKH
`
`OC RECOMMENDATION
`
`050CT-2010
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`SUBMITTED TO 06
`
`04-AUG-2011
`
`SHARMAKH
`
`OC RECOMMENDATION
`
`04~AUG-201 1
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`Januuynao12190PM
`
`mcm-mmmwy
`
`Paps."
`
`Reference ID: 3083898
`
`

`

`FDA CDER E53
`ESTABLISHMENT EVALUATION REQUEST
`DETAI. REPORT
`
`uni—nu:
`
`um:
`
`am: 2050215
`mace.uc.
`
`R02. mm
`macao. PR 0000:;
`
`PB: 1000131011
`
`um.
`
`W
`
`WISH-WWW
`
`MWMTESTER
`
`m mmcrmacwmemmmemmw-zmownsmm
`
`nub:
`
`rmmmeom
`
`'
`
`cum NONE
`
`M1001:
`
`os-oct-amo
`
`wan-111501000
`
`moat-2010 WW
`
`mmmn 14-0612le mend-c
`
`‘
`
`mm mom-2010
`
`mm "wan-2011
`
`os-nov-zmo ‘
`
`1mm"
`
`_
`
`stocm
`
`11115an
`
`Rl-IERNAND
`
`weenaeuoez
`
`
`
`DOmemo"
`
`mum-2011
`
`WITHHOLD
`
`' RHERNAND
`
`
`
`FIFM NOT‘READY
`
`A
`
`“1.312130"
`
`. FOAM-WWW}
`
`M40“
`
`Reference ID: 3083898
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`(5) (4)
`
`'
`25-MAY-2011
`OC RECOMMENDATION
`AFTER REVIEWING THE 483 OBSERVATIONS AND DISCUSSIONS WITH THE INSPECTION
`TEAM. 0C CONCURS WITH THE DISTRICT(,5 WITHHOLD RECOMMENDATION AT THIS TIME.
`THIS RECOMMENDATION IS PENDING A REVIEW OF THE FINALIZED EIR AND THE FIRM¢S
`483 RESPONSE. SEE DO RECOWENDATION FOR REASONS FOR WITHHOLD.
`
`HERTZST
`WITHHQD
`DISTRICT RECOMMENDATION
`
`OC RECOMMENDATION
`
`21-JUL-201 1
`
`WITHHOLD
`
`SMITHDE
`
`DUE TO PDUFA TIMELINE. FDA FORM 483. DRAFT EIR, AND FIRMS 3 RESPONSES WERE
`REVIEWED. DC CONCURS. THROUGH (b) (ODAVE DOLESKI, WITH DO RECOMWNDATION TO
`WITHHOLD BASED ON THE FOLLOWING DEFICIENCIES TO BE RELAYED IN THE CR LETTER:
`
`DISTRICT RECOMIIENDATION
`
`0') (4)
`
`SUBMITTED TO GO
`
`04-AUG-2011
`
`SUBMITTED TO DO
`
`04-AUG-2011
`
`Product SpecIIIc
`
`ASSIGNED INSPECTION TO IB
`
`05—AUG-2011
`
`Produd Specific
`
`SHARMAKH
`
`STOCKM
`
`RHERNAND
`
`DO RECOWENDATION
`
`01-DEC-2011
`
`ACCEPTABLE
`
`RHERNAND
`
`ACCEPTABLE RECOMMENDATION BASED ON INSPECTION CONCLUSION. NAI CONDUCTED
`DURING NOVEMBER 7-16I2011
`
`INSPECTION
`
`OC RECOMMENDATION
`
`MDEC-201‘I
`
`STOCKM
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`amnMZtNH
`
`MGM-WWW
`
`"9050"
`
`Reference ID: 3083898
`
`

`

`Establishmm:
`
`DMF No:
`
`Responsibilities:
`
`E':bnm
`a mom:
`
`Profile:
`
`FDA CDER EES
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`FEI: 1036761
`
`
`CFN: 1036761
`
`MERCK AND CO INC
`
`
`
`4633 MERCK RD W
`
`
`WILSON, NC 278939613
`
`
`
`MBA:
`
`DRUG SUBSTANCE STABILITY TESTER
`
`
`
`FINISHED DOSAGE PACKAGER
`
`
`FINISHED DOSAGE STABILITY TESTER
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DRUG SUBSTANCE (SITAGLIPTIN PHOSPHATE) STABILITY TESTING. (on mom-2010 by K. SHARMA () )
`DRUG PRODUCT PACKAGING AND STABILITY TESTING (on 01-OCT-2010 by K. SHARMA () )
`
`
`
`
`
`
`
`
`
`
`
`
`CONTROL TESTING LABORATORIES "ALSO" (DRUGS)
`OAI Status: NONE
`
`
`
`
`
`
`
`
`
`
`TABLETS. EXTENDED RELEASE
`
`
`
`NONE
`
`mustang;
`
`
`
`
`
`Reggogg Txfl BMW Duclggon V
`
`"Hum umI
`
`_
`
`SUBMITTED TO 0C
`
`
`
`OC RECOMMENDATION
`
`
`SUBMITTED TO 00
`
`
`0C RECOMMENDATION
`
`
`SUBMITTED TO GO
`
`
`
`OC RECOMMENDATION
`
`
`,
`
`05-OCT-2010
`
`06-OCT-2010
`
`04-AUG-2011
`
`04-AUG-2011
`
`05-OCT-2010
`
`05-OCT-2010
`
`Cnagg
`
`.
`
`SHARMAKH
`
`'
`
`STOCKM
`ACCEPTABLE
`
`BASED ON FILE REVIEW
`
`
`
`
`SHARMAKH
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`
`STOCKM
`
`SHARMAKH
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`
`
`STOCKM
`
`SHARMAKH
`
`STOCKM
`
`SUBMITTED TO OC
`
`
`
`04-AUG-2011
`
`OC RECOMMENDATION
`
`
`04-AUG-2011
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`
`
`January 20, 2012 1:30 PM
`
`
`
`
`FDA Confidential - Internal Distribution Only
`
`
`
`
`
`Page 8 of 9
`
`Reference ID: 3083898
`Reference ID: 3083898
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`5:me
`
`CPN: 2510592
`
`Fa: 2510592
`
`MERCK AND co INC
`
`SUMNEYTOWN PIKE sLAzo
`WEST POINT, PA 19486
`
`DNF No:
`
`AADA-
`
`WM:
`
`FINISHED DOSAGE RELEASE TESTER
`
`FINISHED DOSAGE STABILITY TESTER
`
`INTERMEDIATE MANUFACTURER
`
`cm
`
`PROCESS AND ANALYTICAL
`W DRUG PRODUCT MANUFACTURING (METFORMIN HYDROCHLORIDE
`CW
`DEVELOPMENT. MANUFACTURING. REUEASE TESTING AND STABIUTY MONITORING AND TESTING. (an 01—OCT-2010
`by K. SHARMA () )
`TABLETS, EXTENDED RELEASE
`
`OAI 3m:
`
`NONE
`
`mm:
`
`WEE-3219.22.10. WWW—L.
`WWW—w
`SLBMITTED TO DO
`05-OCT-2010
`SHARMAKH
`
`SUBMITTED TO DO
`
`05-OCT-2010
`
`Product Smolfic
`
`STOCKM
`
`DO RECOMRENDATION
`
`18-OCT-2010
`
`ACCEPTABLE
`
`VMATUSOV
`
`PREVIOUS GMP El OF NON-STERILE AND STERILE DRUG OPERATIONS (INCLUDING
`MANUFACTURING OF TABLETS AND CAPSULES) IS DATED 8/3-18/10. PLEASE NOTE THAT
`THIS El IS NOT YET ENDORSED BUT IT APPEARS THAT IT WILL BE CLASSIFIED NAI OR VAI.
`PROFILE CLASSES SIMILAR TC
`(5) (4) WERE COVERED AND ARE DOCUMENTED
`AS ACCEPTABLE. PRCFILE CLASS (5) (”MILL BE COVERED DURING THE NEXT SCHEDULED
`INSPECTION. THERE ARE NO PENDING REGULATORY ACTIONS WITH RESPECT TO
`PROWCTION OF NON-STERILE OR STERILE DRUG PRODUCTS. ALTHOUGH CONCURENT EI
`CONDUCTED BY TEAM BIO DID REVEAL SIGNIFICANT GMP VIOLATIONS ON THE VACCINE
`MANUFACTURING SIDE. PER THE LEAD PHI-DO CSO. THE UNCOVERED DEFICIENCIES
`\N'T IM’ACT MANUFACTURING OF STERILE AND NON-STERILE DRUGS.
`
`BASED ON FILE REVIEW
`
`18-OCT-2010
`OC RECOWENDATION
`SEE DO MILESTONE COMMENTS
`
`SUBMITTED TO OC
`
`04-AUG-2011
`
`INYARDA
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`SHARMAKH
`
`STOCKM
`
`10-Day Letter
`04-AUGQO11
`SLBMITTED TO DO
`PAI WAS WAIVED DURING FIRST REVIEW CYCLE. IT APPEARS AS THOUGH AN INSPECTION
`WAS JUST COMPLETED AT THIS FACILITY; NOT SURE IF THIS PRODUCT WAS COVERED.
`
`onus-2011
`DO RECOMMENDATION
`ONGOING GMP INSPECTION OF THIS SITE THAT COMMENCED ON 7/18/11 UNCOVERED
`SIGNIFICANT GMP DEFICIENCIES INCLUDING MULTIPLE EXAMPLES OF INADEOUATE
`INVESTIGATIONS AND INSUFFICIENT CORRECTIVE ACTIONS m RESPONSE TO VARIOUS
`PRODUCT CONTAMINATION INCIDENCES. SIMILAR VIOLATIONS WERE UNCOVERED
`DURING THE MOST RECENT 2010 TEAM BIO INSPECTION OF THE VACCINE
`MANUFACTURING SIDE. ”APPEARS THAT THE EI WlL BE CLASSIFIED OAI WITH THE
`RECOMMENDATION OF FURTHER REGULATORY ACTION.
`
`' VMATUSOV
`wrrHHOLD
`INADEOUATE QA FUNCTIONS
`
`07-OCT-2011
`OC RECOMMENDATION
`CDER OC IS REVIEWING A WRNG LTR RECOMMENDATION.
`
`CRUZC
`WITHHOLD
`DISTRICT RECOMMENDATION
`
`10-Day Later
`OHM-2012
`SUBMITTED TO DO
`PLEASE REEVALUATE THE COMPLIANCE STATUS PER EMAIL FROM STEVE HERTZ
`
`SMITHDE
`
`DO RECOMMENDATION
`
`WAN-2012
`
`THE PREVIOUS GMP El DATED 7/18-8/11/11 IS CLASSIFIED VAI (INITIAL CLASSIFICATION OF
`nAI WAS CHANGED TO VAI ON 1/5/12 BY PHI CB BASED ON THE PROPOSED ISSUANCE OF
`E UL WHICH IS CURRENTLY IN CDER). PROFILE CLASSES SIMILAR TO
`(”WI
`
`ACCEPTABLE
`
`VMATUSOV
`
`BASED ON FILE REVIEW
`
`anumm
`
`FDACMI-MIWM
`
`Poo-7°“
`
`Reference ID: 3083898
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`WERE COVERED AND ARE DOCUMENTED AS ACCEPTABLE. PROFILE CLASSGMQ WILL BE
`COVERED DURING THE NEXT SCHEDULED El. THERE ARE NO PENDING REGULATORY
`ACTIONS WITH RESPECT TO NON-STERILE OR STERILE DRUG PRODUCTS. ,
`
`0C RECOMMENDATION
`
`WAN-2012
`
`I
`
`NYARDA
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`Jumnflfltflm
`
`FDACW-mwwwy
`
`P0908“,
`
`Reference ID: 3083898
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Esubllshmom:
`
`cs»: 2623436
`
`FEI: 2623436
`
`MERCK SHARP AND DOHME QUIMICA
`
`RD 2, KM 56.7
`BARCELONETA, PR 00617
`
`our No:
`
`AADA:
`
`Rape-manna:
`
`DRUG SUBSTANCE MANUFACTURER
`
`DRUG SUBSTANCE PACKAGER
`
`DRUG SUBSTANCE RELEASE TESTER
`
`mum DRUG SUBSTANCE (SITAGLIF'TIN PHOSPHATE) MANUFACTURING, PACKAGING AND RELEASE TESTING (on o1-ocr.
`CW
`2010 bv K SHARMA n I
`man:
`
`OAI 3mm: NONE
`
`"9“)
`
`m—m W mm mm 22.9% L...
`sma—______——_—_— MW
`SUBMITTED TO 00
`05-OCT-2010
`8
`
`OC RECOMMENDATION
`
`05-OCTo2010
`
`SUBMITTED TO 06
`
`04-AUG-2011
`
`SUBMITTED TO DO
`
`04-AUG-2011
`
`10-Day Letter
`
`ACCEPTABLE
`BASED ON PROFILE
`
`STOCKM
`
`SHARMAKH
`
`STOCKM
`
`05-AUG-2011
`DO RECOWENDATION
`ACCEPTABLE RECOMMENDATION BASED ON PREVIOUS INSPECTION RESULTS. LAST El
`r)ATED 3131/2011 AND CLASSIFIED AS VAI. CSN PROFILE ACCEPTABLE.
`
`RHERNAND
`ACCEPTABLE
`BASED ON FILE REVIEW
`
`L
`
`ECONMENDATION
`
`17-AUG-2131 1
`
`TOMOUSEM
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`qunmz1zuru
`
`Pmcmm-mmmmu
`
`P390901!
`
`Reference ID: 3083898
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`02/07/2012
`
`Reference ID: 3083898
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Silver Spring, MD 20993
`
`
`
`
`
`
`
`CMC Memo to File
`
`
`NDA
`26 Jan 2012
`Merck Sharp & Dohme Corp.
`Janumet XR (Sitagliptin, Metformin HCl Fixed Dose Combinations;
`50/500, 50/1000, and 100/1000 mg sitagliptin/metformin XR)
`Complete Response recommendation
`Dr. Olen Stephens
`
`To:
`Date
`Sponsor:
`Drug:
`Subject
`Reviewer
`
`
`Pursuant the overall “acceptable” recommendation given on 25-Jan-2012 for the
`
`manufacturing facilities by the Office of Compliance, CMC recommends that NDA application
`202-270 be approved. All labeling changes have been communicated to the applicant through
`the clinical project manager. There are no pending CMC review deficiencies.
`
`
`
`
`
`
`
`
`
`
`HFD-/Division File
`HFD-510
`HFD-510/R. Chiang
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Olen Stephens, Ph.D.
`Chemistry Reviewer
`
`
`
`
`
`
`Ali Al-Hakim, Ph.D.
`Branch VII Chief, ONDQA
`
`
`
`Reference ID: 3077369
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`OLEN M STEPHENS
`01/26/2012
`Overall quality recommendation is for approval. OC issued acceptable recommendation 25-Jan-
`2012. No CMC deficiencies remain.
`
`ALI H AL HAKIM
`01/26/2012
`
`Reference ID: 3077369
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Silver Spring, MD 20993
`
`
`
`
`
`
`
`CMC Memo to File
`
`
`NDA
`4 Jan 2012
`Merck Sharp & Dohme Corp.
`Janumet XR (Sitagliptin, Metformin HCl Fixed Dose Combinations;
`50/500, 50/1000, and 100/1000 mg sitagliptin/metformin XR)
`Complete Response recommendation
`Dr. Olen Stephens
`
`To:
`Date
`Sponsor:
`Drug:
`Subject
`Reviewer
`
`
`Pursuant the overall “withhold” recommendation given on 4-Dec-2011 for the
`
`manufacturing facilities by the Office of Compliance, CMC recommends that NDA application
`202-270 receive a complete response. All labeling changes have been communicated to the
`applicant through the clinical project manager. There are no pending CMC review deficiencies.
`
`
`
`
`
`
`
`
`
`
`HFD-/Division File
`HFD-510
`HFD-510/R. Chiang
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`Olen Stephens, Ph.D.
`Chemistry Reviewer
`
`
`
`
`
`
`Ali Al-Hakim, Ph.D.
`Branch VII Chief, ONDQA
`
`
`
`Reference ID: 3066856
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`OLEN M STEPHENS
`01/04/2012
`CMC recommendation: complete response pursuant to "withhold" recommendation by OC
`
`ALI H AL HAKIM
`01/04/2012
`
`Reference ID: 3066856
`
`

`

`
`
`NDA 202270
`
`Janumet XR
`(Sitagliptin and Metformin HCl Fixed Dose Combinations;
`50/500, 50/1000, and 100/1000 mg
`sitagliptin/metformin HCl Extended Release)
`
`Summary of the Basis for the Recommended Action
` from Chemistry, Manufacturing, and Controls
`
`
`
`Applicant: Merck Sharp & Dohme Corp.
`P.O. Box 1000, UG2CD-48
`North Wales, PA 19454-1099
`
`
`Indication: Management of type 2 diabetes mellitus.
`
`Presentation: The drug product will be packaged in opaque high-density
`
`
`
`polyethylene (HDPE) bottles containing
` to match the corresponding
`
`
`Each bottle will have a
`
`
`bottle sizes. The 1000-count pharmacy bottles will have
`
`
`
` and the 30-, 60-, 90-, and 180-count configurations
`
`will have
`
`
`
`Biopharm Recommendation:
`Acceptable
`Establishments Evaluation Report (EER) Recommendation: Withhold (5/25/11)
`
`Consults:
`
`
`
`
`
`
`
`
`
`Not requested (categorical exclusion per
`21CFR25.31 granted)
`N/A
`Not requested
`N/A
`N/A
`Acceptable
`
`August 11, 2010
`N/A
`None at this time.
`
`
`
`EA –
`
`
`
`
`
`
`Statistics –
`Methods Validation –
`Clinical Pharm –
`
`Microbiology –
`
`Pharm Toxicology –
`
`
`
`
`
`Original Submission:
`
`
`Re-submissions:
`
`Post-Approval CMC Agreements:
`
`Drug Substances
`
`
`
`Reference ID: 2962358
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202-270
`
`Summary Basis of Recommended Action – CMC
`
`P. 2
`
`Both drug substances, Sitagliptin and Metformin HCl, are active ingredients of
`previously approved drug products. Sitagliptin is the active ingredient in Januvia®
`(sitagliptin) Tablets (NDA 21-995), and metformin is the active ingredient in
`Glumetza (extended release metformin HCl reference) Tablets. The applicant is
`including all sitagliptin phosphate drug substance information by reference to NDA
`21-995 (held by the same applicant). The metformin HCl active ingredient is
` was reviewed and found adequate.
`controlled by DMF
`. DMF
`
`Chemical Structures, Molecular Formula, and Chemical Names
`
`Metformin Hydrochloride
`
`
`
`
`
`
`N,N-dimethylimidodicarbonimidic diamide hydrochloride
`Molecular Formula: C4H11N5 • HCl
`Molecular Mass: 165.63 g/mol
`
`
`Sitagliptin Phosphate
`
`
`
`
`
`
`
`
`
`7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-
`tetrahydro-[3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1)
`monohydrate
`Molecular Formula: C16H15F6N5O • H3PO4 • H2O
`Molecular Mass: 523.32 g/mol
`Conclusion: Drug substances are satisfactory
`
`
`
`
`Reference ID: 2962358
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202-270
`
`Summary Basis of Recommended Action – CMC
`
`P. 3
`
`Drug product
`The drug products proposed in NDA 202-270 are designed to provide immediate
`release for sitagliptin and extended release for metformin HCl. The applicant is
`including all sitagliptin phosphate drug substance information by reference to NDA
`21-995 (held by the same applicant). The metformin HCl active ingredient is
`controlled by DMF
`. The
` film coats are supported by DMF
`other components are compendial and controlled as per their respective
`monographs
`
`Three fixed dose combinations (FDC) have been developed for marketing: 50/500,
`50/1000, and 100/1000 (mg sitagliptin as free base/mg metformin hydrochloride).
`The applicant is granted a biowaiver for the 50 mg/1000 mg potency. JANUMET®
`XR (sitagliptin/metformin XR) tablets will be packaged in 7- and 14- (all strengths),
`30- (100/1000 mg tablets only), 60- (50/500 mg and 50 /1000 mg tablets), 90-
`(100/1000 mg tablets only), 180- (50/500 mg and 50 /1000 mg tablets), and 1000-(all
`strengths) count HDPE bottles.
`
`The manufacturing process can be divided into
`
` All
`
`
`
`
`
`
`
`
`
`
`Specifications for the drug products include Assay, degradation products, dose
`uniformity, identity, dissolution, propyl gallate assay
`
`
`The provided stability data provided in the NDA support an expiry dating
`period of 24 months.
`Drug product is satisfactory
`
`Overall Conclusion:
`There are no pending CMC review deficiencies. However, CMC recommends complete
`response due to OC "withhold" recommendation.
`
`
`Ali Al-Hakim, Ph.D.
`Branch Chief, Division III
`ONDQA/CDER/FDA
`
`
`
`
`
`
`
`
`
`Reference ID: 2962358
`
`(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/
`----------------------------------------------------
`
`ALI H AL HAKIM
`06/17/2011
`
`Reference ID: 2962358
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Silver Spring, MD 20993
`
`
`
`
`
`
`
`CMC Memo to File
`
`
`NDA
`25 May 2011
`Merck Sharp & Dohme Corp.
`Janumet XR (Sitagliptin, Metformin HCl Fixed Dose Combinations;
`50/500, 50/1000, and 100/1000 mg sitagliptin/metformin XR)
`Complete Response recommendation
`Dr. Olen Stephens
`
`To:
`Date
`Sponsor:
`Drug:
`Subject
`Reviewer
`
`
`Pursuant the overall “withhold” recommendation given on 25-May-2011 for the
`
`manufacturing facilities by the Office of Compliance, CMC recommends that NDA application
`202-270 receive a complete response. All labeling changes have been communicated to the
`applicant through the clinical project manager. The biopharmaceutics reviewer rendered an
`“acceptable” evaluation of the biowaiver request and has come to agreement for the dissolution
`specifications (refer to biopharmaceutics review filed in DARRTS 19-May-2011 by Dr. Sandra
`Suarez ). There are no pending CMC review deficiencies.
`
`
`
`
`
`
`
`
`
`
`HFD-/Division File
`HFD-510
`HFD-510/R. Chiang
`
`
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`
`
`Olen Stephens, Ph.D.
`Chemistry Reviewer
`
`
`
`
`
`
`Ali Al-Hakim, Ph.D.
`Branch VII Chief, ONDQA
`
`
`
`Reference ID: 2951931
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`OLEN M STEPHENS
`05/25/2011
`CMC recommendation: complete response due to OC "withhold" recommendation.
`
`ALI H AL HAKIM
`05/25/2011
`
`Reference ID: 2951931
`
`

`

`
`
`NDA 202-270
`
`Janumet XR (Sitagliptin, Metformin HCI Fixed Dose
`Combinations; 50/500, 50I1000, and 100l1000 mg
`sitagliptinlmetformin XR)
`
`Merck Sharp & Dohme Corp.
`
`Olen M. Stephens
`Pre-Marketing Division III for the
`
`Division of Metabolic and Endocrinology Products
`
`Reference ID: 2939562
`
`

`

`
`
`Table of Contents
`
`Table of Contents ....................................................................................... 2
`
`Chemistry Review Data Sheet................................................................... 3
`
`The Executive Summary............................................................................ 7
`
`I. Recommendations ..................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability .......................................................... 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable .................................................................................... 7
`
`II. Summary of Chemistry Assessments ........................................................................ 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 ........................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ................................................ 9
`
`III. Administrative ............................................................................................................ 9
`
`A. Reviewer’s Signature ......................................................................................................... 9
`
`B. Endorsement Block............................................................................................................ 9
`
`C. CC Block............................................................................................................................ 9
`
`Chemistry Assessment ........................................................................... 1 0
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data10
`
`S DRUG SUBSTANCE [Name, Manufacturer] .................................................................. 10
`
`P DRUG PRODUCT [Name, Dosage form] ....................................................................... 13
`
`A APPENDICES ................................................................................................................ 72
`
`R REGIONAL INFORMATION .......................................................................................... 72
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ...................... 74
`
`A. Labeling & Package Insert .............................................................................................. 74
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ...................................... 74
`
`Ill.
`
`List Of Deficiencies To Be Communicated ......................................................... 74
`
`Reference ID: 2939562
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1- NDA 202-270
`
`2- REVIEW #: 1
`
`3. REVIEW DATE: 28—Apr—2010
`
`4. REVIEWER: Olen M. Stephens
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`NA
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission(s) Reviewed
`Original Submission (0000)
`Amendment (0001 )
`Amendment (0010)
`Amendment (001 1)
`
`Document Date
`24-Sep—201 0
`30—Sep—201 0
`1 1-Apr-201 1
`1 1-Apr-201 1
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address:
`
`Merck Sharp & Dohme Corp.
`
`PO. Box 1000, UGZCD-48
`
`North Wales, PA 19454—1099
`
`Representative:
`
`Richard J. Swanson, Ph.D., Sr. Director,
`Regulatory Affairs
`
`Reference ID: 2939562
`
`Page 3 of 74
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Telephone:
`
`267-305-6871
`
`8. DRUG PRODUCT NAME/CODEfTYPE:
`
`a) Proprietary Name: JANUMET XR
`b) Non-Proprietary Name (USAN): Sitagliptin/Metformin Hydrochloride Fixed Dose
`Combination
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(2) — Glumetza (extended
`release metformin -- Depomed)
`
`10. PHARMACOL. CATEGORY: Sitagliptin is a dipeptidyl peptidase—4
`inhibitor (DPP—4 inhibitor); metformin suppresses hepatic glucose
`production and sensitizes liver, muscle and fat tissue to insulin
`
`11. DOSAGE FORM: Tablet
`
`12. STRENGTH/POTENCY: 50/500, 50/1000, 100/1000 mg
`Sitagliptin/metformin XR
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. RX/OTC DISPENSED:
`
`X RX
`
`OTC
`
`15- SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`
`
`SPOTS product — Form Completed
`
`
`X
`
`Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`Metformin Hydrochloride
`
`Reference ID: 2939562
`
`Page 4 0f 74
`
`

`

`
`
`Chemistry Review Data Sheet
`
`CH3
`l
`N
`
`H
`N
`
`/
`
`H3C
`
`NH
`
`NH
`
`NH
`
`2
`
`.
`
`HCl
`
`1 ,1-Dimethylbiguanide hydrochloride
`C4H11N50HCI; MW 165.63
`
`
`
`Sita li tin Phos hate
`
`- H20
`
`' H3PO4
`
`7-[(3R)—3-amino-1 -oxo-4-(2,4,5-trifluorophenyl)butyl]—5,6,7,8—tetrahydro-[3-
`(trifluoromethyl)-1,2,4—triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate
`C16H15F6N500H3P040H20; MW 523.32
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`Feb-10-201 1
`
`DATE REVIEW
`COMPLETED
`
`Feb-10-201 1
`
`Feb-10-201 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")
`
`2Adequate, Inadequate, or NIA (There is enough data in the application, therefore the
`DMF did not need to be reviewed)
`
`Reference ID: 2939562
`
`Page 5 of 74
`
`

`

`
`
`Chemistry Review Data Sheet
`
`18. STATUS:
`
`
`ONDC:
`
`CONSULTSI CMC
`
`RELATED
`
`REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`-—m———
`
`acce table
`No outstandin issues——
`
`Reference ID: 2939562
`
`Page 6 0f 74
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 202-270
`
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From a CMC review perspective, the NDA is recommended for approval, pending
`an Acceptable recommendation from ONDQA Biopharmaceutics.
`
`This recommendation does not incorporate any potential facility inspection issues
`(an overall recommendation from the Office of Compliance is outstanding.)
`
`The following recommendations are pending but will not have an impact on the
`specific findings discussed in this CMC review:
`
`1. Office of Compliance — GMP status of the commercial manufacturing and
`testing facilities listed in the NDA.
`2. ONDQA Biopharm Staff — biowaver for the 50 mg/1000 mg strength
`3. OSE — Labeling.
`
`JANUMET® XR
`the
`for
`grantable
`period
`dating
`expiration
`The
`(sitagliptin/metformin XR) tablets in 7-, 14-, 30—, 60, 90-, 180-, and 1000—count
`HDPE bottles is 24 months with storage conditions of 25°C (77°F); excursions
`permitted to 15- 30°C (59—86°F) [see USP Controlled Room Temperature].
`“"0
`
`The applicant will submit data to support a site change for the metforrgig
`
`as a CBE-30 after NDA approval. The submission will
`include 3 months of accelerated stability data for the three batches at each
`strength (long term data will be sent to the annual report), dissolution data, and
`cGMP certification for the new site. This proposal is described in 3.2.P.3.3.3.
`Even though the drug product is a modified-release product, the site change will
`require supportive data as described in SUPAC-IR. Refer below for justification in
`R2.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments,
`Agreements, and/or Risk Management Steps, if Approvable
`
`Reference ID: 2939562
`
`Page 7 of 74
`
`

`

`
`
`Executive Summary Section
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`NDA 202-270 is submitted by Merck for Janumet XR (sitagliptin/metfonnin HCI XR)
`tablets for oral administration, containing either 50 mg/500 mg, 50 mg/1000 mg or
`100 mg/1000 mg fixed dose combination (FDC) of sitagliptin/metformin HCI. Both
`drug substances are active ingredients of previously approved drug products.
`Sitagliptin is the active ingredient in Januvia® (sitagliptin) Tablets (NDA 21 -995),
`and metformin is the active ingredient in Glumetza (extended release metformin
`HCI reference) Tablets. The proposed indication is for treatment of patients with
`type 2 diabetes. The FDC drug products proposed in NBA 202—270 are designed
`to provide immediate release for sitagliptin and extended release for metformin
`HCI. The applicant is including all sitagliptin phosphate drug substance information
`by reference to NBA 21-995 (held by the same applicant. The metformin HCI
`
`active ingredient is controlled by DMF — The* film coats are
`
`supported by DMF - All other componen s are compen Ia and controlled as
`per their respective monographs.
`
`Three fixed dose combinations (FDC) have been developed for marketing: 50/500,
`50/1000, and 100/1000 (mg sitagliptin as free base/mg metformin hydrochloride).
`The applicant is seeking a biowaiver for the 50 mg/1000 mg potency. JANUMET®
`XR (sitagliptinlmetformin XR) tablets will be packaged in 7-, 14-, 30- (100l1000 mg
`tablet only), 60- (50/500 mg and 50 /1000 mg tablets), 90- (100/1000 mg tablet
`only), 180- (50/500 mg and 50 /1000 mg tablets), and 1000-count HDPE bottles.
`The 7- and 14-count h sician samples and 1000—count pharmacy bottles
`
`
`
`
`d; the 30-, 60, 90-, and 180-count configurations
`
`rocess can be divided into
`
`
`
`con Irrne
`process.
`
`will be used for the manufacturing
`
`as
`
`B. Description of How the Drug Product is Intended to be Used
`
`Janumet XR tablets will be dispensed by prescription only for the management of
`type 2 diabetes mellitus. The recommended dose one tablet daily with food. The
`dose strength, 50 mgl500 mg, 50 mg/1000 mg or 100 mg/1000 mg
`(sitagliptin/metfonnin), will be prescribed on an individual basis by the clinician
`depending on the patient’s individual glycemic control, renal function, and drug
`
`Reference ID: 2939562
`
`Page 8 of 74
`
`

`

`""""‘ — ”""‘
`.
`CHEMISTRY REVIEW
`-
`!
`
`Executive Summary Section
`
`product tolerability. The drug product should be stored are 25°C (77°F) with
`excursions permitted to 15- 30°C (59-86°F)
`[see USP Controlled Room
`Temperature].
`A 1000-count pharmacy bulk package and 7- and 14-count
`physician samples will also be available.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`Chemistry, Manufacturing and Controls deficiencies for the dmg product were
`communicated to the applicant
`(14—MAR—2011) and have been sufficiently
`addressed.
`
`The following recommendations are pending but will not have an impact on the
`specific findings discussed in this CMC review:
`
`1. Office of Compliance — GMP status of the commercial manufacturing
`and testing facilities listed in the NBA.
`2. ONDQA Biophann Staff — Biowaiver for the 50 mgl1000 mg strength
`and IVIVC for dissolution.
`
`3. OSE — Labeling.
`
`Ill. Administrative
`
`A. Reviewer’s Signature
`
`Olen M. Stephens
`
`B. Endorsement Block
`
`ChemistName/Date: Olen M. Stephens
`ChemistryTeamLeaderName/Date: Dr. Ali Al-Hakim
`ProjectManagerName/Date: Raymond Chiang
`
`C. CC Block
`
`
`
`Reference ID: 2939562
`
`Page 9 of 74
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`OLEN M STEPHENS
`04/28/2011
`CMC recommendation is for approval pending accept