CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`209091Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`QUALITY REVIEW
`
`Recommendation:
`
`APPROVAL
`
`{including the Overall Manufacturing Inspection Recommendation!
`
`NDA 209091
`
`Review #1
`
`Review Date (see last page)
`
`Dru Name/Dosa_e Form saxagliptin and dapagliflozin tablets
`m_ 5/10 mg/mg
`Route of Administration_
`
`mm: mum _
`
`SUBMISSION S REVIEWED
`0000
`
`DOCUMENT DATE
`4/27/2016
`
`0 uali
`
`' Review Team
`
`DISCIPLINE m DIVISION/OFFICE
`Application Technical Lead
`Suong (Su) Tran
`New Drug Products H/ONDP
`Regulatory Business Process
`Anika Lalmansingh
`Regulatory Business Process
`Manager
`Management I/OPRO
`Drug Product
`New Drug Products lI/ONDP
`
`Inspectional Assessment/OFF
`
`John Amartey
`Vipulchandra Dholakia
`
`

`

` “mt"
`QUALITY REVIEW
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs: Adequate (see OPQ review ofNDA-)
`
`B. Other Documents:
`
`W APPLICATION DESCRIPTION
`—I
`saxagliptin and dapagliflozin tablets (same product, same applicant)
`
`2. CONSULTS: not applicable
`
`Executive Summary
`
`Recommendation and Conclusion on Approvability
`1.
`The recommendation from the Office of Pharmaceutical Quality (including the 11/21/16
`Overall Manufacturing Inspection Recommendation) is for APPROVAL.
`
`II.
`
`Summary of Quality Assessment
`
`A. Product Overview
`
`This is a 505(b)(l) application for a fixed dose combination of two approved drug
`substances, saxagliptin and dapagliflozin, 5 mg and 10 mg. This is not an NME
`application because the applicant has several approved NDAs for these drug
`substances.
`
`The same product in this new NDA was previously submitted in NDA
`same a
`licant. NDA- received a Complete Response on 10/15 2015
`OPQ review recommended “approval” at the time of the action
`with no pending Quality issue.
`
`b the
`
`B. Quality Assessment Overview
`
`The CMC information in the new NDA and the reviousl
`
`reviewed NDA
`
`
`
`

`

`QUALITY REVIEW
`
`The OPQ review ofNBA 209091 consists of the drug product review of the new and
`ted information listed above and a cross-reference to the OPQ review ofNBA
`for the evaluation of all other Quality information. The Overall
`Manufacturing Inspection Recommendation is updated on 11/21/16 for “approval”.
`
`
`
`

`

`QUALITY REVIEW
`
`CHAPTERS: Primary Quality Assessment
`
`”(4’)
`
`Chapter I: Drug Substance (see OPQ Review of NDA
`Chaper II: Drug Product
`Chapter 111: Environmental Assessment (see OPQ Review ofNDA
`Chapter IV: Labeling
`(mo)
`Chapter V: Process (see OPQ Review ofNDA
`om)
`Chapter VI: Facilities (see OPQ Review of NDA
`”(4’)
`Chapter VII: Biopharmaceutics (see OPQ Review of NDA
`(mo)
`Chapter VIII: Iincrobiology (see OPQ Review of NDA
`Attachment 1: Final Risk Assessment (see OPQ Review ofNDA
`
`(mo)
`
`om)
`
`

`

` QUALITY REVIEW
`
`CHAPTER II: Drug Product
`and
`
`CHAPTER IV: Labeling
`
`

`

`
`
`Drug Product Review – Memorandum
`
`FROM:
`
`John K. Amartey, PhD
`
`
`
`
`
`CMC-Reviewer/DNDPII/Branch VI
`
`THROUGH: Danae Christodoulou, PhD
`
`
`
`TO:
`
`
`
`
`
`Acting Branch Chief/DNDPII/Branch VI
`
`NDA 209091
`
`DATE:
`
`08/14/2016
`
`SUBJECT:
`
`Saxagliptin/Dapagliflozin Fixed-Dose Combination (5 mg/10 mg) tablets
`
`
`
`INTRODUCTION:
`
`The NDA 209091 is seeking market approval for saxagliptin 5 mg and dapagliflozin 10 mg fixed-
`dose combination (FDC) tablet. The product is indicated as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Dapagliflozin is an
`inhibitor of the sodium-glucose co-transporter 2 (SGLT2). The SGLT2 inhibitors reduce
`hyperglycemia by promoting glucose excretion by the kidney. Saxagliptin is dipeptidyl peptidase
`4 (DPP4) inhibitor. DPP4 inhibitors improve the beta-cell sensitivity to glucose, increase insulin
`secretion, and decrease glucagon secretion. These inhibitors therefore complement the action
`of the SGLT2 inhibitors in reducing hyperglycemia. The two drug substances have been
`approved in several NDA such as in 2009 NDA 22350 to market Onglyza (saxagliptin), 2010 NDA
`200678 Kombiglyze XR (saxagliptin/metformin HCl). Dapagliflozin is approved as Farxiga in 2014
`NDA 202293. The FDC is submitted in NDA
`
`
`
`
`In NDA 209091 the applicant seeks approval for a single strength saxagliptin 5 mg/ dapagliflozin
`10 mg FDC. The drug product is packaged in the container closure systems: HDPE bottle and
` blisters. Portions of this NDA have been previously
`also in
`submitted to NDA
`
`
`
`
`Page 1 of 4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Referenced DMFs: The cited DMFs are listed in the table below and are adequate.
`
`ADEQUATE
`
`9/25/2014
`
`
`10/21/2015
`
`ADEQUATE
`
`Description:
`
`
`
`
`Revision of Drug Product sections:
`
`Specifications:
`
`
`— The sample chromatogram presented indicated that the method is suitable
`for the intended use.
`
`Excipients:
`
`There are no novel excipients. The non-compendial excipients are well controlled (CoA s are
`
`provided in the application). The analytical methods used are based on compendial procedures
`
`and no need for validation.
`
`Page 2 of 4
`
`

`

`
`
`Table 3.2.P.5.4—l: Batch Information {or San 5/Dapa10
`
`Site of
`Date of
`Drag Substance Batch Used
`Batch
`
`Number —— Manulacture Manufacture
`
`Batch Size
`(tablets)
`
`Use of Batch
`
`4Dslssls'
`
`3E7699NT
`
`4ca9280N
`
`41>7s4o4sa
`
`3D77208UN
`
`4(389280N
`
`«3888988
`
`3D77208UN
`
`«38928014 3082341
`
`21-71028
`
`21-72891
`
`3032340
`
`2F71027
`
`21771344
`
`33737255/
`
`3032339c
`
`21-71026
`
`21-71034
`
`’ Coated -tablels
`b Clinical applies batch number - coated
`
`blets
`
`Stability:
`
`Long term stability:
`
`The long term stability data on three batches of the saxa 5 mg/ dapa10 mg product packaged in
`the- blisters (5°C, 25°C/60%RH and 30°C/75%RH), show that there is essentially little or
`no change in mean potency (saxa and dapa), impurities (saxa and dapa),—
`— mean hardness, disintegration time, or appearance through the 24
`months test period (the longest real time data). The data is evaluated in accordance with ICH
`
`Q1E. The results show that the predicted values at 36 months are within the acceptance limits
`
`under the long term stability storage conditions. Similar results are observed for the saxa 5 mg/
`
`dapa 10 mg tablets when packaged in the HDPE bottles and stored at the long term condition of
`
`25°C/60%RH for 24 months and at accelerated condition 40°C/75%RH for 6 months. Based on
`
`the real data presented the proposed 36 months shelf-life is justified.
`
`Post—approval stability protocol and commitment:
`
`The applicant commits to continue with the long-term stability studies following the protocol
`
`presented in the application.
`
`Comparability Protocol:
`
`Page 3 of 4
`
`

`

`NEW lABElING:
`
`The proposed- blisters package label is shown below. The label presented in the
`application is for a tablet count of 7 as a Physician sample. In the labeling the section 3: Dosage
`
`Forms and Strength and the section 11: Description lists only the 5 mg/10 mg strength. In
`
`section 16: How Supplied/Storage and Handling the three bottle size tablet counts of 30, 90 and
`
`500 are described.
`
`The carton has label is not changed
`
`
`
`RECOMMENDATION: APPROVAL
`
`Page 4 of 4
`
`

`

`Danae
`Christodoulou
`
`Digitally signed by Danae Christodoulou
`Date: 10/04/2016 12 26:24PM
`GUID: 5050dd27000012a4c69bfc70b47660b7
`
`John
`Amartey
`
`Digitally signed by John Amartey
`Date: 10/04/2016 10:18:35AM
`GUID: 54061eab0009a3906521deca6e5fda70
`
`

`

`Su (Suong)
`Tran
`
`Digitally signed by Su (Suong) Tran
`Date: 1/04/2017 11:14:56AM
`GUID: 508da71f00029ec8b75e233f12b15339
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`NDA FILING REVIEW
`
`_
`.
`.
`ApplIcatIon #' 209091
`Applicant: Astra Zeneca
`Submission Type:
`505 b 1 —not NME
`
`Chemical Type: 4
`
`Established/Proper Name:
`' tin and da a I liflozin
`Dosage Form: tablet
`_
`Strength(s). 5 mgl10 mg
`
`am
`
`Unapproved NDA
`
`A. FILING CONCLUSION
`
`Cross Referenced Applications:
`Approved NDA 22350, NDA 200678, NDA 202293, and NDA
`205649
`
`FILED? I Ifthe application is not fileable
`
`_
`
`DOES THE OFFICE OF
`
`PHARMACEUTICAL
`
`QUALITY RECOMIVIEND
`THE APPLICATION TO BE
`
`x
`
`from the product quality
`perspective, state the reasons and
`provide filing comments to be
`sent to the A I.licant
`
`Are there any potential 1eview
`issues to be forwarded to the
`
`Applicant not including any
`
`til—incomments stated above?
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`NDA FILING REVIEW
`
`B.
`
`OVERVIEW OF CRITICAL PRODUCT QUALITY REVIEW CONSIDERATIONS
`
`This is a 505(b)(I) applicationfor afixed dose combination oftwo approved drug substances,
`saxagliptin and dapagliflozin, 5 mg and 10 mg. This is not an NlllE application because the applicant
`has several approved NDAsfor these drugs.
`
`which received a Com Iete Res onse on 10/15/2015 due to
`
`o The newNDA 209091, with the onli one strenith oi 5/10, is ior the indication oftype 2 diabetes
`
`The CMC information
`
`
`
`Plan or the 0P review:
`
`with thefollowing addition:
`reference is made to the OPQ review ofNBA
`1. Drugproduct reviewer to evaluate the new/additional infomtation as summarized above.
`2. Facilities reviewer to evaluate all commercial testing, manufacturing, andpackagingfacilities
`currently in the NDA.
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`NDA FILING REVIEW
`
`I—"m_m_
`GENERAL/ADMINISTRATIVE
`
`c. FILING CONSIDERATIONS
`
`1.
`
`2
`
`Has an environmental assessment report (NB/IE.
`API with estrogenic. androgenic. or thyroid activity;
`API derived from plants and animals) or appropriate
`categorical exclusion (21 CFR 25.31 AND 25.15(d)
`been provided?
`For DMFs. are DMF #5 identified and
`
`authorization letter(s) from the US agent provided
`in the a I
`I lication and referenced DMF?
`
`3
`
`Is the Quality Overall Summary (QOS) organized
`adequately and legible? Is there sufiicient
`
`information in the Q08 to conduct a review?
`FACILITY INFORMATION
`
`NDA 202293 is referenced for all CMC
`
`information on the drug substance
`dapagliflozin.
`NDA 22350 is referenced for all CMC
`
`infornmtion on the drug substance
`dapagliflozin.
`
`See the DRUG PRODUCT review of NDA
`
`(b) (4) for the same product- recommending
`approval with no pending issue.
`(5)“)
`
`See the Biopharmaceutics review ofNDA
`('9 (4) for the same product— recommendin
`approval with no pending issue
`
`adequately and legible? Is there sufficient
`information in this section to conduct a review?
`
`IstheDrugProductsection[3.2.P]organized II.
`
`BIOPHARMACEUTICS
`
`If the Biopharmaceutics team is responsible for
`reviewing the in vivo BA or BE studies:
`0 Does the application contain the complete BA/BE
`data?
`0 Are the PK files in the correct format?
`
`0 Is an inspection request needed for the BE
`study(ies) and complete clinical site information
`provided?
`
`0'"
`
`Are drug substance manufacturing sites, drug
`product manufacturing sites. and additional
`manufacturing. packaging and control/testing
`laboratory sites identified on FDA Form 356h or
`associated continuation sheet with complete
`identifying information?
`
`Is a statement provided that all facilities are ready
`for GMP inspection at the time of submission?
`For BLA:
`
`El
`El
`
`Is a manufacturing schedule provided?
`Is the schedule feasible to conduct an
`ins I ction within the review c cle?
`DRUG SUBSTANCE INFORMATION
`
`Is the Drug Substance section [3.2.S] organized
`adequately and legible? Is there sufficient
`information in this section to conduct a review?
`
`DRUG PRODUCT INFORMATION
`
`5.
`
`7.
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`NDA FILING REVIEW
`
`
`C. FILING CONSIDERATIONS
`
`Are there adequate in vitro and/or in vivo data
`supporting the bridging of formulations throughout
`the drug product’s development and/or
`manufacturing changes to the clinical product?
`(Note whether the to-be—marketedproduct is the
`same roduct used in the ivotal clinical studies
`
`Does the application include a biowaiver request?
`If yes. are supportive data provided as per the type
`of waiver requested under the CFR to support the
`re a nested waiver? Note the CFR section cited.
`
`For a modified release dosage form. does the
`application include information/data on the in-vitro
`alcohol dose-d n n in 1 . tential?
`
`12. For an extended release dosage form.15 there
`enough information to assess the extended release
`desi-:41 tion claim as 1 a the CFR?
`
`.
`
`Is there a claim or request for BCS I designation? If
`yes. is there sufficient permeability solubility
`stabili
`. and dissolution data?
`REGIONAL INFORMATION AND APPENDICES
`
`
`
`Are any study reports or published articles in a
`foreign language? If yes. has the translated version
`been included in the submission for review?
`
`15. Are Executed Batch Records for drug substance (if
`applicable) and drug product available?
`
`16.
`
`If applicable. is the required information provided
`in 3.2.A for Biotech Products?
`
`7. For Biotech Products. is sufficient information
`
`provided1n compoliance with 21 CFR 610.9 and
`601 .2(a)?
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`NDA FILING REVIEW
`
`mtg-unsust—
`m5
`
`Suong {mat-umm
`Tran _S fifihmD‘ magnum.”
`m
`
`Application Technical Lead
`
`Suong (Su) Tran, PhD
`
`

`

`QUALITY ASSESSNIENT
`
`Recommendation:
`
`APPROVAL
`
`(5) (4)
`
`NBA
`
`Review #1
`
`ReVieW Date: (see page 5)
`
`Drug Name/Dosage
`Form
`
`saxagliptin and dapagliflozin tablets
`
`Route of
`
`Administration
`
`5/10m 111
`
`oral
`
`Rx/OTC Dis - ensed
`
`a I
`
`I licable
`
`SUBIVIISSION(S) REVIEWED
`‘Y
`.
`
`DOCI‘BIENT DATE
`12/152011
`
`[
`
`I
`[
`
`
`
`Amendment
`Auicndulcul
`
`I
`J
`
`5 "I 12015
`691553015
`
`Quali Review Team
`——-mm-
`—_——
`
`ORA Lead ——
`
`Business Process Manager
`
`Keni-Ann Jennings
`Anika Lalmansin n
`
`A lication Technical Lead
`
`OPRO/RBPMI
`
`ONDP/DNDPII
`
`Laborato
`
`OTR ——
`
`

`

` “me"
`QUALITY REVIEW
`
`Table of Contents
`
`Table of Contents .......................................................................................... 2
`
`SW........................................................................... 3
`
`Executive Summary ...................................................................................... 4
`
`Prima
`
`uali Review............................................................................... 6
`
`ASSESSMENT OF THE DRUG SUBSTANCE ............................................................... 7
`
`ASSESSIVIENT OF THE DRUG PRODUCT .................................................................... 8
`
`ASSESSMENT OF THE PROCESS ................................................................................ 32
`
`ASSESSMENT OF THE FACILITHES ............................................................................ 64
`
`ASSESSIVIENT OF BIOPHARMACEUTIC S ................................................................. 68
`
`ASSESSMENT OF MICROBIOLOGY ........................................................................... 93
`
`APPENDICES .................................................................................................................. 96
`
`ASSESSMENT OF ENVIRONMENTAL ANALYSIS .................................................. 97
`
`L
`
`Review of Common Technical Docmnent- uali
`
`Ctd- Module 1 ................ 98
`
`Labeling & Package Insert ................................................................................................ 99
`
`Q
`
`List of Deficiencies To Be Communicated......................................................... 106
`
`E Attachments ........................................................................................................ 106
`
`

`

`QUALITY REVIEW
`
`Quality Review Data Sheet
`
`1.
`
`2.
`
`LEGAL BASIS FOR SUBMISSION: n/a
`
`RELATED/SUPPORTING DOCUNIENTS:
`
`1.
`DMFs:
`Reviewed b Dru
`Product Reviewer
`
`
`
`ITEM
`
`TYPE HOLDER
`
`
`REFERENCED
`
`
`
`COMPLETED
`(5X
`
`
`
`
`
`
`
`
`I Adequate. Adequate with Information Request. Deficient. or N/A (There is enough data in the application.
`therefore the DMI" did not need to be reviewed)
`
`
`
`
`
`
`
`
`EEEEEEZ
`
`information in NDA
`
`Adequate
`NDA review date
`-_
`3t’21t2012
`
`sufiicient
`
`Nt’A
`
`3M 1»"05
`
`Adequate
`
`NDA review date
`
`4w’24t’12
`
`Adequate
`
`NDA review date
`
`sufficient
`information in NDA
`NtA
`
`sufficient
`information in NDA
`
`2.
`
`Other Documents:
`
`DOCUMENT APPLICATION NUMBER
`22350 samea-”licant
`202293 same a licant
`
`DESCRIPTION
`
`Farxia daa-liflozin NDA
`
`205649 (same applicant)
`
`Xigduo (dapagliflozin/metformin hydrochloride
`extended release
`
`3.
`
`CONSULTS:
`
`RECOMMENDATION _m
`STATUS
`DISCIPLINE
`—————
`thcologynomology————
`———_—
`
`—————
`
`Other
`
`

`

`QUALITY REVIEW
`
`Recommendation
`
`Executive Summary
`
`Recommendation and Conclusion on Approvability
`
`NDA
`(m4) is recommended for approval from the Quality perspective.
`There is no unresolved deficiency.
`Labeling comments will be finalized via the 0ND Division review process.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approved — n/a
`
`Summary of Quality Assessment
`Drug Substance Quality Summary
`Reference is made to the Quality reviews of the approved NDA 22350
`saxagliptin and approved NDA 202293 dapagliflozin.
`Drug Product Quality Summary
`Strength: 5 /10 mg/mg saxagliptin/dapagliflozin
`Description/Commercial Image: light brown to brown, biconvex round fihn—
`coated tablets,
`(5)9) “1122” printed on the other side, in
`blue ink
`
`Summary of Product Design n/a
`List of Excipients: anhydrous lactose, croscannellose sodium, iron oxides,
`magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, polyethylene
`glycol, silicon dioxide, talc, and titanium dioxide.
`Process Selection (see section “Process” in this review):
`
`(m4)
`
`Container Closure: bottles of 30-, 90-, and 500-count in bottles for commercial
`distlibution, and 7-count blisters as samples
`Expiration Date & Storage Conditions: 8 months when stored at room
`temperature (20-25 °C).
`List of co-packaged components n/a
`
`Summary of Drug Product Intended Use
`
`1.
`
`1.
`
`2.
`
`3.
`1.
`
`2.
`1.
`2.
`
`3.
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Proprietary Nameormenmgmaw —
`NonFromm-mmorthenmsrroaw—
`Non Proprietary Name of the Drug Substance
`Saxa . 1i .fin and (13.3 .
`'flozin
`
`5 /10m in saxali-Itin/daa 'flozin
`
`Provost"! Indifffionfi) including Intended
`Pam” Populamn
`
`Adjunct to diet and exercise to improve
`glycemic control in adutls with type 2
`diabetes mellitus
`
`MaximumDailyDose
`
`

`

` """"‘
`QUALITY REVIEW
`
`Alternative Methods «Administration
`
`10.
`
`Biopharmaceutics Considerations (see section “Biopharmaceutics” in this
`review)
`1. BCS Classification: Saxagliptin BCS III, dapagliflozin BCS III
`
`2. Biowaivers/Biostudies
`
`l.
`
`The results from BE study CV181341 are acceptable. The Saxa
`5/ Dapa 10 mg FDC tablets are bioequivalent
`to the respective strengths of Saxa and Dapa mono-tablets in fasted
`healthy adults. There was no meaningful effect on the peak or total
`exposure of saxagliptin due to administration in the fed state. High fat
`meal, however, reduced the peak exposure of dapagliflozin by
`approximately 50%.
`In conclusion, the combination of both
`saxagliptin and dapagliflozin together in one FDC tablet obtains the
`similar conclusion of the food effect on respective mono-tablet stated
`in their labeling. See labeling details on food effects of respective
`mono-tablets.
`
`l l.
`
`12.
`
`Novel Approaches n/a
`
`13.
`
`Any Special Product Quality Labeling Recommendations n/a
`
`14.
`
`Life Cycle Knowledge Information (see Attachment B)
`
`
`
`

`

`
`
`ASSESSRIENT OF BIOPHAR\IACEUTICS
`
`In this submission,
`
`and exercise to '
`
`the Applicant seeks approval for
`saxagliptin (5mg) and dapagliflozin (10 mg), as adjunct to diet
`rove l cemic contIol in adults with
`
`e 2 diabetes mellitus
`
`-68-
`
`

`

`QUALITY REVIEW
`
`
`
`

`

`Similarl , durin the long-term stabili
`
`test for the ro
`
`sed formulations, the drug
`
`Table 8. Justification for Using Disintegration as a Surrogate for Dissolution for
`
`Saxagliptin/Dapagliflozin Proposed Commercial Tablets
`
`According to ICH Q6A guidance and its Decision Tree #7(1) (Table 8), the proposed
`Saxa/Dapa commercial tablets meet all the criteria shown in Table 8 below, and are
`considered qualified for using disintegration as a surrogate for dissolution.
`
`method
`
`Criteria Jusflneaflon for Sangflptin/Dapagllflozil
`Pro
`d Commercial Tablets
`
`ICH Q6A Decision Tree # 7(1)
`
`Thedosagefiormisnoldesignedtoproducemdified
`release.
`
`The drug solubility at 37:0.S°C is high (dose/solubility
`S ZSOmL) dironghout the physiological pH range (pl-I
`1.2 -6.8).
`
`Greater than 80% dissolution is achieved in 15 minutes
`at pH 1.2. 4.0. and 6.8.
`
`Arehtionshhhasbeenestablishedbetweendissohm’on
`anddisintegntionordisimegntionisshowntobeme
`discriminatingdnndissolmion
`
`The Applicant tested the discriminability of both dissolution method and disintegration
`
`

`

` QUALITY REVIEW
`
`3. Disintegration acceptance criteria
`
`The maximum disintegration time was
`
`minutes at initial and showed some
`
`Disintegration in lieu of dissolution is used as QC method because of meeting the criteria
`as shown in Table 8. The proposed acceptance criterion for disintegration time is-
`minutes at 37°C water.
`
`tablets stored under all long-term storage conditions through 12 months.
`
`variability with values ranging from
`
`minutes with no major trend observed for
`
`-82-
`
`

`

`QUALITY REVIEW
`
`
`
`

`

`QUALITY REVIEW
`
`Furthermore, the statistical analysis conducted by the Applicant based on stability data
`shows that
`M“) the disintegration time at release is
`(me
`
`minutes. The upper side of the 95% confidence/99% coverage tolerance interval of the
`release disintegration time is m<9minutes Statistical analysis of the trend of
`
`disintegration over time found no significant increase in the disintegration time. Overall,
`the proposed acceptance criterion «0(4) minutes at 37°C of water is acceptable.
`
`PART 2. Review of BE studies and Biowaiver request
`
`BE Studies
`
`Bioequivalence study CV181341 has been conducted to demonstrate bioequivalence
`M" Saxa 5/ Dapa 10 mg tablets compared with the
`(m4) Saxa and Dapa in fasted state. The food effect on the FDC tablets
`
`was also studied.
`
`The saxagliptin and dapagliflozin in study CV181341 were analyzed by LC/MS/MS, and
`the Applicant provided the validation report and summary as follows:
`Dnculncul
`Sample
`RcIrcuion
`Standard
`Assay precision
`Accuracy
`cuulrul
`matrix
`model,
`curve
`(° u( V)
`(‘0
`number
`“righting
`mule
`II" iztinn)
`(ng‘mL)
`0 L50
`
`.,_
`
`. . _
`
`74 1'.
`
`'
`
`0 I 100
`
`L
`
`-'
`
`_
`
`‘
`
`-
`
`1.' I
`
`1
`
`'1
`
`n
`
`3
`
`a
`
`r
`
`_\
`
`‘V 3
`
`-
`
`.
`
`‘
`
`subnhly for
`saxagliptin and 4 ‘
`hr {0, BM$751084A9
`401 dav; LTS al -
`.‘0"(' 6 ryrlex PT
`a! 20°C post
`prepauuu- \labllllv
`31 h: at RT
`RT = .‘4 h 5 cyclrs
`FfT al »10‘C & -
`70”C 337 divs LTS
`:1 -_‘0‘(' & -70”C,
`Posl Preparative
`mum \Inlulm' 7.‘
`hm RT and H] h Ill
`3 lo 81‘
`RT-6h.FT-5
`cvcles at 20’( J:
`7012 m daVs
`LTE II 301' and
`615 a.» at .70°('.
`Post Preparative
`cxuncl sllbllrlv,
`9| 3* "mm at .’ lo
`B‘T
`
`.
`
`CV13] '91
`
`('\'181I9l
`('\'18134l
`
`.
`
`C\’18134l
`
`
`
`930037127
`
`Sanghpun
`
`Human
`
`‘-}{vdmxy
`saxagliptin
`
`plasma
`EDTA
`
`-
`
`a
`
`:
`
`Lllll'fll.
`‘
`.
`“C out!
`mem.
`l“(('on(b:
`
`9‘0065686
`
`Duplghflonn
`
`Human
`plasma
`EDTA
`
`'
`
`'
`
`Luna“. l x1
`
`930081711
`
`,
`
`me,’
`‘
`-
`_
`l u m“
`
`2
`
`L'“““-_
`1 “("01)“-
`
`
`
`
`
`
`
`The incurred sample reproducibility is determined with 10% of the study sample
`reassayed, the ISR met the acceptance criteria of ”(0%. The analytical report for the BE
`study is acceptable.
`
`The harmacokinetic PK results from the stud cohort l are shown as below:
`
`1 Page has been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`_ 85 _
`
`

`

`QUALITY REVIEW
`
`Table 2 : Statistical Analysis Results of Dapagliflozin for Cohort 2 (dosed with Saxa
`
`5/Dapa 10 FDC or Saxagliptin 5 +Dapaglifloxin 10 mg)
`
`PK Parameter
`
`(‘nnx (ng‘mL)
`
`Auqon
`(“5“ “'L)
`
`Treatment and
`Comparison
`D (Sm - Dapa fasted)
`E(Sa.u.Dapa fasted)
`F (SmDapz fed)
`E versus D
`F versus E
`
`D (Sax: « Dapa firsted)
`E (Sm Dapa fasted)
`F (Sm Dapa fed)
`E wrsus D
`F versus E
`
`Adj listed Geometric
`Mean
`149
`141
`913
`0 9-16
`0 648
`
`577
`598
`557
`,
`
`.
`
`90' o ('1
`
`(134. 166)
`(115‘158)
`(811.103)
`(0 878‘ 1.019)
`(0 565. 0 743)
`
`(542. 615)
`(562. 636)
`(5:6. 589)
`(1010. 1062)
`(0 908. 0955)
`
`_’
`
`(559‘ 635)
`D61“ - Dapa filsted)
`(579. 656)
`E (Saanapa fasted)
`(550. 615)
`I -
`F (SamDapa fed)
`(1008‘ 1.063)
`1035
`E versus D
`(0 919‘ 0 968)
`0 943
`1' versus E
`Treatment D: 5mg saxagliptin - 10mg dapagltflozin tablets under tasted conditions
`Treatment E San S'Dapa IO FDC tablet under fasted conditions
`Treatment F' Sun 5 Dip: 10 FDC tablet lmder fed conditions
`
`The reviewer’s own analysis is as follows:
`
`0923-0976
`
`—— 0.944
`—— 0.648
`
`0.87&1.016
`0565-0-743
`
`—— 0.949
`
`1 Page has been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`_ 87 _
`
`

`

`QUALITY REVIEW
`
`Table 4 : Statistical Analysis Results of Saxagliptin for Cohort 2 (Dosed with Saxa 5
`mg/Dapa 10 mg FDC or Saxagliptin 5 mg + Dapaglifloxin 10 mg)
`.u
`€-
`
`90' 'o (“I
`Adjusted Geometlit
`Treatment and
`PK Parameter
`
`Comparison
`Mean
`D (Sax: — Dapa fasted)
`26 1
`
`Cmax (ng'mL)
`
`(23 7. 28 8)
`
`
`
`E (SauDapa tasted)
`F (San-Dam fed)
`Evemst
`F versus E
`
`D (Sm - Dapa fasted)
`E (SmDapa fasted)
`F (San Dapa fed)
`1a vetsus D
`FversusE
`
`17.6
`35 6
`1059
`0 925
`
`95 s
`96 4
`111
`1.007
`1155
`
`(2512. 30.3)
`(23 3. 28 2)
`(0 9911 139)
`(0 8371 11022
`
`(90 3. 10:)
`(90,71 10:)
`(1061 117)
`(0.973. 1704:)
`(1117.1.194)
`
`AU(‘(0~'[)
`(“En“)
`
`(91 ,81 IO!)
`97 3
`D (Sax: - Dapa fasted)
`(9191 104)
`97 6
`E (SnaDapa fasted)
`(107. 119)
`113
`F(Sa.ulDapa fed]
`(01969. 1,038)
`1.003
`E \‘eisus D
`(11181 1194)
`1155
`FvususE
`Treatment D: S—mg sasagliptin — 10mg dapagliflozin lablets under fasted conditiom
`Treatment E‘ Sam 5 Dapa 10 FDC tablet under fasted conditions
`Imminent F. Sam 5 Dapa 10 FDC tablet undet fed condiums
`
`The reviewer’s own analysis is as follows:
`
`Adjusted
`Geometric mean
`
`90% CI
`
`.987-1.129
`
`.837-1.028
`
`.969-l.050
`
`.115-1.200
`
`.965—1.045
`
`.116-1.200
`
`-89-
`
`

`

`"""“""
`
`
`QUALITY REVIEW
`
`“"5""
`
`As all above tables show, although there are slightly diflerences in the values calculated
`by the reviewer and values provided by the Applicant, the overall trend and conclusion
`are the same:
`
`1. The
`
`Saxa 5/ Dapa 10 mg FDC tablets are bioequivalent to the
`Saxa an Dapa mono-tablets in fasted healthy adults.
`2. There was no meaningful effect on the peak or total exposure of saxagliptin due to
`administration in the fed state.
`
`3. High fat meal, however, reduced the peak exposure of dapagliflozin by approximately
`
`50%.
`
`In conclusion, the combination ofboth saxagliptin and dapagliflozin together in
`
`one FDC tablet obtains the similar conclusion of the food effect on respective mono-
`
`Saxa 5.0 mg
`
`tablet stated in their labeling. Please refer to labeling details on food effects of respective
`mono-tablets.
`
`Biowaiver Issues
`
`The bioequivalence studies on]
`
`-90-
`
`

`

` QUALITY REVIEW
`
`Bioequivalence
`.
`Studies Submitted in NDAs or DVDs-General Considerations, the justifications from the
`Applicant are acceptable.
`
`Table 5 The Com osition 0f Saxa/Da a FDC Tablet
`
`-91-
`
`

`

`QUALITY REVIEW
`
`OVERALL ASSESSNIENT AND SIGNATURES:
`
`BIOPHARMACEUTICS
`
`Reviewer’s Assessment and Si nature: (Peng Duan)
`
`Digitally signed by Peng Duan -5
`ON: c:US. o:US. Government. ou:HHS, ou=FDA,
`
`Pe n g Du a n — ”lemma
`
`Date: 2015.07.20 1023:41 -04‘00'
`
`1. The dissolution method (as below) and the application of disintegration test in lieu
`
`of dissolution method are acceptable.
`2. The acceptance criterion for disintegration time
`
`(m4) minutes at 37°C of water is
`
`appropriate.
`3. The results from BE study CV181341 are acceptable;
`a. The
`M4) Saxa 5/ Dapa 10 mg FDC tablets are bioequivalent
`to the
`(m4) Saxa and Dapa mono-tablets in fasted healthy adults.
`b. There was no meaningful effect on the peak or total exposure of saxagliptin due
`to administration in the fed state.
`
`c. High fat meal, however, reduced the peak exposure of dapagliflozin by
`approximately 50%.
`In conclusion, the combination of both saxagliptin and
`dapagliflozin together in one FDC tablet obtains the similar conclusion of the food
`
`effect on respective mono-tablet stated in their labeling. Please refer to labeling
`details on food effects of respective mono-tablets.
`
`4.
`
`5. The following dissolution method is reviewed and accepted.
`
`USP Apparatus
`
`Agitation Speed
`(RPM)
`
`Media Volume
`(mL)
`
`Temperature
`( C)
`
`6. Finally, the proposed disintegration method and its acceptance criterion (W)
`minutes at 37°C of water are acceptable for implementation upon NDA approval.
`
`Supervisor Comments and Concurrence: (Tien Mien Chen)
`
`
`
`I
`
`The Biopharmaceutics review is complete and I concur.
`.
`.
`Digitally signed by Tlenmien Chen -S
`I e n m I e n DN:c=US, o=U.S.Govemment,
`ou=HHS, ou=FDA, ou=People,
`cn=Tienmien Chen -S,
`135
`0.9.2342.19200300.100.1.1=1300073
`Date: 2015.08.10 11:50:01 —04'00'
`
`-
`C h e n S
`
`-92-
`
`

`

` QUALITY REVIEW
`
`ASSESSNIENT OF MICROBIOLOGY
`
`1. Are the tests and proposed acceptance criteria for microbial burden adequate for
`assuring the microbial quality of the drug product?
`
`Applicant’s Response: This can be adopted fiom the QbR-QOS and Module 3 provided
`fiom the firm.
`
`Reviewer’s Assessment: Adequate
`
`0 The excipients used in the manufacture of Saxa/Dapa are tested for microbial
`'
`b theirre
`tiveco
`dialr
`'
`cuts.
`
`- and in- blister packs
`
`0 Bulk contaian of tablets at the manufac
`
`'
`
`site include
`
`r appropriate packaging
`
`- The Saxa/Dapa tablets are packaged in HDPE bottles
`
`-93-
`
`

`

`QUALITY REVIEW
`
`
`
`

`

`QUALITY REVIEW
`
`space and change control program in terms of validation?
`
`
`Is the proposed container/closure system for the drug product validated to
`flmction as a barrier to microbial ingress? What is the container/closure design
`
`2.
`
`

`

`QUALITY REVIEW
`
`Applicant’s Response: This can be adopted from the QbR—QOS and Module 3 provided
`from the firm.
`
`Reviewer’s Assessment: Adequate
`
`The commercial presentation for Saxa/Dapa tablets is
`(HDPE) bottle
`
`(I’m high density polyethylene
`"’""
`
`Saxa/Dapa tablets may also be presented in
`
`blisters.
`
`The suitability of the packaging components and container closure systems has been
`demonstrated by the results of the stability studies reported in Section 3.2.P.8, Stability.
`
`The materials used in the fabrication of the packaging components conform to the
`requirements in the applicable sections of the Code of Federal Registration, Title 21,
`Indirect Food Additives. Letters from the vendors with the specific references of
`compliance are provided on the following pages. The Drug Master Files (DMF) and
`Letters of Authorization (LOA) for the primary packaging components are provided in
`Module 1.4.1.
`
` A
`
`APPENDICES
`
`A.2
`
`Adventitious Agents Safety Evaluation
`
`3. Are any materials used for the manufactlu'e of the drug substance or drug product
`of biological origin or derived from biological som‘ces? If the drug product
`contains material som‘ced from animals, what docmnentation is provided to
`assure a low risk of virus or prion contamination (causative agent of TSE)?
`
`Applicant’s Response: This can be adopted from the QbR-QOS and Module 3 provided
`from the film.
`
`Reviewer’s Assessment: Adequate
`
`ma) statements are rovided.
`
`The adventitious Agents
`Safety Evaluation reports are provided in 3.2.R. Regional Information section. The
`
`4.
`
`If any of the materials used for the manufactlu'e of the drug substance or drug
`product are of biological origin or derived from biological sources, what diug
`substance/drug product processing steps assure microbiological (viral) safety of
`
`-96-
`
`

`

` QUALITY REVIEW
`
`the component(s) and how are the viral inactivation/clearance capacity of these
`processes validated?
`
`Applicant’s Response: This can be adopted from the QbR-QOS and Module 3 provided
`from the firm.
`
` Reviewer’s Assessment: NIA
`
`OVERALL ASSESSMENT AND SIGNATURES: MICROBIOLOGY
`
`
`
`
`
`
`
`ASSESSNIENT OF ENVIRONNIENTAL ANALYSIS
`
`1.
`
`2.
`
`Is the applicant’s claim for categorical exclusion acceptable?
`Yes.
`
`Is the applicant’s Environmental Assessment adequate for approval of the
`application?
`m
`
`-97-
`
`

`

`“""""
`mam
`
`QUALITY REVIEW
`
`""“‘""
`u—I-n-M—n—n-
`
`‘
`
`I. Review of Common Technical Document-Quality (Ctd-Q) Module 1
`
`Labeling & Package Insert
`1. Package Insert
`(a) “Highlights” Section (21CFR 201.57(a))
`
`QI‘ERN(saxagliptinanddapagliflozin)isindicatedasanad'
`
`cttodietandexerciseto'
`
`ve
`
`comic
`
`Lmntatlonso Use:
`
`
`
`“WM,2mmmmwe“
`
`
`
`
`[jg’T
`
`:1;
`
`If 7
`
`’51
`
`net title,D .
`
`; name 201.57 a2
`
`established name
`
`Established Name:
`
`Saxagliptin/Dapagliflozin Fixed Dose
`Combination
`
`mm
`'
`
`'
`
`'
`
`Contmlled drug
`substance symbol (if
`my licable
`
`Route: Oral
`
`N/A
`
`A concise summary of Fixed dose combination tablets have
`been developed
`
`
`
`5 mg saxagliptin/lo mg
`dapagliflozin.
`
`Conclusion:
`
`Dapagliflozin).'l‘he information
`
`is adequate.
`
`the applicant
`
`(b) “Full Prescribing Information” Section
`
`# 3: Dosage Forms and Strengt_hs [21CFR 201.571cfl4n
`
`QTERN tablets containing 5
`round, film-coated tablet, with
`
`' tin and 10
`
`' ozin are light brown to brown, biconvex,
`“l 122” printed on the other side, in blue ink.
`
`-98-
`
`

`

`QUALITY REVIEW
`
`\ “emu...“
`
`above.
`
`_ Information Provided in NBA
`Available dosa ~ e forms
`QTERN Tablets
`Strengths: in metric system
`
`”(9
`
`5 mg Saxa/10 mg Dapa
`A description of the identifying Table 3.3.P. l-l of the application
`characteristics of the dosage
`describes in detail the information.
`forms, including shape, col