CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`200678Orig1s000
`
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`NDA 200-678
`
`kombiglyzeTM XR
`(saxagliptin and metformin HCl extended-release)
`Tablets
`
`Summary of the Basis for the Recommended Action
` from Chemistry, Manufacturing, and Controls
`
`
`Applicant: Bristol-Myers Squibb Co.
`P.O. Box 4000,
`Princeton, NJ 08543-4000
`Background: This NDA is submitted as a 505(b)(1) application. The drug product
`is a new Fixed Dose Combination. The reference drugs are:
`Onglyza® (saxagliptin) Tablets (NDA 22-350), Glycophage
`(metformin HCl) tablets (NDA 20-357) and Glycophage XR
`(metformin HCl) Tablets (NDA 21-202).
`
`
`Indication: The drug product is indicated as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes when
`treatment with both saxagliptin and metformin is appropriate.
`
`
`Presentation: The proposed drug product will be packaged in high density
`polyethylene (HDPE) bottles with a two-piece, child-resistant,
`continuous-thread closure having an aluminum-foil induction seal
`(inner seal). Larger bottles (e.g., pharmacy or institutional
`packages) have a one piece continuous-thread closure with an
`aluminum-foil induction seal (inner seal). The bottles contain
`activated carbon/silica gel desiccant packet(s). Physician samples
`are packaged in
` blister.
`
`
`
`Establishments Evaluation Report (EER) Status:
`
`Consults:
`
`
`
`
`
`
`EA –
`
`
`Statistics –
`Methods Validation –
`Biopharm–
`
`
`Microbiology –
`
`Pharm Toxicology –
`
`Acceptable
`
`Acceptable
`N/A
`Not recommended
`Acceptable
`Acceptable
`N/A
`
`
`
`Original Submission:
`
`
`
`
`
`December 30, 2009
`
`(b) (4)
`
`

`

`NDA 200-678
`
`Summary Basis of Recommended Action – CMC
`
`P. 2
`
`N/A
`None at this time.
`
`Re-submissions:
`
`
`
`Post-Approval CMC Agreements:
`
`Drug Substances:
`Saxagliptin
`All information regarding the physicochemical properties, impurities, method of
`synthesis and purification, process controls, control of raw materials, container
`closure system and stability of saxagliptin are provided in NDA 22-350 for
`Onglyza® (saxagliptin) Tablets (from the same applicant as this NDA). The drug
`substance saxagliptin will be manufactured at the BMS facility in Sword, Ireland.
`The retest period for saxagliptin is
` when stored at USP controlled cold
`temperature i.e. between 2° and 8°C (36° and 46°F); excursions permitted
`between 0° and 15°C (32° and 59°F).
`Structural formula, chemical name, molecular weight and molecular formula
`Saxagliptin monohydrate
`
`
`
`
`
`
`
`
`
`
`
`Chemical Name: (1S,3S,5S)-2-[(2S)-2-Amino-2-(3 hydroxytricyclo [3.3.1.13,7]dec-1-
`yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate.
`Molecular Weight: 333.43 (315.41 anhydrous) g/mol
`Chemical Formula: C18H25N3O2•H2O
`
`Metformin HCl
`All information regarding the physicochemical properties, impurities, method of
`synthesis and purification, process controls, control of raw materials, container
`closure system and stability of metformin HCl are provided in the Drug Master
`Files (DMFs)
` both held by
` The drug substance is
`supplied as metformin HCl
`. Both of these DMFs
`were reviewed and found adequate. The retest period for metformin
`hydrochloride is
` when stored in the
` described in DMF
` at long term ICH room temperature conditions.
`Structural formula, chemical name, molecular weight and molecular formula
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 200-678
`
`Summary Basis of Recommended Action – CMC
`
`P. 3
`
`
`Chemical name: 1,1- Dimethylbiguanide hydrochloride
`Molecular Weight: 165.6 g/mol
`Molecular Formula: C4H12ClN5
`
`Conclusion: The Drug Substances are adequate.
`
`
`Drug Product:
`The proposed drug product is a fixed dose combination of saxagliptin and
`metformin HCl. The proposed strengths are: saxagliptin 5 mg/metformin HCl
`500 mg, saxagliptin 5 mg/metformin HCl 1000 mg, saxagliptin 2.5
`mg/metformin HCl 1000 mg.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The application contains a Quality by Design (QbD) approach used during
`
`development of the drug product. This approach was utilized for the
`The QbD implementation approach was similar to the QbD
`approach used in the approved product ONGLYZA. ONGLYZA was developed
`following the QbD paradigm and was a part of FDA’s CMC Pilot Program.
`The provided stability data support a shelf life of 15 months for the blisters and
`21 months for the bottles, when stored at 20° to 25°C (68°-77°F); excursions
`permitted between 15 and 30°C (59 and 86°F) (see USP Controlled Room
`Temperature).
`
`Conclusion: The Drug Product is adequate.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 200-678
`
`Summary Basis of Recommended Action – CMC
`
`P. 4
`
`Overall Conclusion: From the CMC point of view, the application is
`recommended for APPROVAL.
`
`
`Ali Al-Hakim, Ph.D.
`Branch Chief, Division III
`ONDQA/CDRR/FDA
`
`
`
`
`
`
`
`
`Container label for the 5 mg/1000 mg presentation
`
`
`(b) (4)
`
`

`

`NDA 200-678
`
`Summary Basis of Recommended Action – CMC
`
`P. 5
`
`
`
`
`
`
`
`APPEARS THIS WAY ON
`ORIGINAL
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`10/26/2010
`
`Reference ID: 2855006
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 200-678
`
`
`Tradename™
` (saxagliptin and metformin HCl extended-release)
`Tablets
`
`
`Bristol-Myers Squibb Co.
`
`
`
`
`Elsbeth Chikhale, Ph.D.
`ONDQA – Div III – Branch VII
`and
`Sharmista Chatterjee, Ph.D.
`ONDQA – Science and Policy
`
`for
`Division of Metabolism and Endocrinology Products
`
`
`
`
`
`
`
`
`1
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`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 ..................................................................................................... 7
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................7
`B. Description of How the Drug Product is Intended to be Used ........................................................9
`C. Basis for Approvability or Not-Approval Recommendation.........................................................10
`
`III. Administrative....................................................................................................................................... 10
`A. Reviewer’s Signature.....................................................................................................................10
`B. Endorsement Block.........................................................................................................................10
`C. CC Block ........................................................................................................................................10
`
`Chemistry Assessment.......................................................................................... 11
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.................... 11
` DRUG SUBSTANCE [Saxagliptin, Swords Laboratories]......................................................11
`S
`S
` DRUG SUBSTANCE [Metformin HCl,
`] ..................16
`P
` DRUG PRODUCT [Tradename, Tablet] .................................................................................21
`A
` APPENDICES..........................................................................................................................81
`R
` REGIONAL INFORMATION.................................................................................................81
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ............................................... 82
`A. Labeling & Package Insert ............................................................................................................82
`B. Environmental Assessment Or Claim Of Categorical Exclusion ...................................................82
`
` III. List Of Information Requests Communicated ................................................................................. N/A
`
`
`
`
`2
`
`(b) (4)
`
`

`

`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`1. NDA 200-678
`
`
`2. REVIEW #: 1
`
`
`3. REVIEW DATE: 30-SEP-2010
`
`
`4. REVIEWER: Elsbeth Chikhale, Ph.D.
`
`
`
`5. PREVIOUS DOCUMENTS: N/A
`
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`Document Date:
`Submission(s) Reviewed:
`29-DEC-2009
`Original
`Amendment to original1
`23-APR-2010
`Amendment to original1
`28-MAY-2010
`Amendment to original2
`03-AUG-2010
`Amendment to original3
`24-SEP-2010
`1) The 4/23/10 and 5/28/10 amendments provides for updated drug product stability data
`and a response to the CMC IR dated 3/12/10
`2) The 8/03/10 amendment provides for a response to the CMC IR dated 7/2/10
`3) The 9/24/10 amendment provides for a response to the CMC IR dated 9/10/10
`
`
`7. NAME & ADDRESS OF APPLICANT:
`Name: Bristol-Myers-Squibb Co.
`
`Address: P.O. Box 4000, Princeton, NJ 08543-4000
`
` Representative: Pamela J. Smith, M.D., Group Director, GRS
`
`Telephone: (609) 252-4000
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`a) Proprietary Name: Tradename™
`b) Non-Proprietary Name (USAN): saxagliptin and metformin HCl
`c) Code Name/#:
`
`d) Chem. Type/Submission Priority:
`• Chem. Type: 4 (new combination)
`• Submission Priority: Standard
`
`3
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: This NDA is submitted as a 505(b)(1)
`application. The drug product is a new Fixed Dose Combination (FDC). The reference
`drugs are: Onglyza® (saxagliptin) Tablets (NDA 22-350), Glycophage (metformin HCl)
`tablets (NDA 20-357) and Glycophage XR (metformin HCl) Tablets (NDA 21-202).
`
`
`
`
`10. PHARMACOL. CATEGORY:
`Saxagliptin is a dipeptidyl peptidase 4 (DPP4) inhibitor.
`Metformin HCl is biguanide antihyperglycemic agent.
`
`
`
`
`
`11. DOSAGE FORM: Tablet
`
`
`12. STRENGTH/POTENCY: 5 mg saxagliptin/ 500 mg metformin HCl
`5 mg saxagliptin/ 1000 mg metformin HCl
`2.5 mg saxagliptin/ 1000 mg metformin HCl
`
`
`
`
`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:
`
`Saxagliptin monohydrate:
`
`
`Chemical name: (1S,3S,5S)-2-[(2S)-2-Amino-2-(3 hydroxytricyclo [3.3.1.13,7]dec-1-
`yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate;
`Molecular formula: C18H25N3O2•H2O
`Molecular weight: 333.43 (315.41 anhydrous) g/mol
`
`4 4
`
`

`

`
`
`
`
`Metformin HCl:
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`Chemical name: 1,1-Dimethylbiguanide hydrochloride
`Molecular Formula: Molecular formula: C4H12ClN5
`Molecular Weight: 165.6 g/mol
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`A. DMFs:
`
`DMF # TYPE HOLDER
`
`ITEM
`REFERENCED
`
`CODE1 STATUS2
`
`COMMENTS
`
`DATE
`REVIEW
`COMPLETED
`Adequate November 13,
`2007
`
`II
`
`II
`
`3
`
`1
`
`Adequate
`
`Reviewed by
`Aloka Srinivasan,
`Ph.D.
`June 29, 2010 Reviewed by
`Elsbeth Chikhale,
`Ph.D.
`
`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 relevant revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other
`
` 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
`NDA
`NDA
`
`APPLICATION
`NUMBER
`22-350
`20-357
`
`NDA
`
`21-202
`
`
`
`5 5
`
`DESCRIPTION
`Onglyza (saxagliptin) Tablets
`Glycophage (metformin HCl)
`Tablets
`Glycophage XR (metformin HCl)
`Tablets
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`18. STATUS:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Acceptable
`Biopharmaceutics
`N/A
`Biometrics
`Acceptable
`EES
`N/A
`Pharm/Tox
`N/A
`CDRH
`Clinical Pharmacology N/A
`Methods Validation
`FDA revalidation is not
`needed
`Pending
`Pending
`Categorical exclusion
`granted (consult not needed)
`Approval
`
`RECOMMENDATION
`
`DMEPA
`DDMAC
`EA
`
`Microbiology
`
`
`
`19. ORDER OF REVIEW: N/A
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`DATE
`
`REVIEWER
`
`9/27/10
`
`2/9/10
`
`
`
`9/30/10
`
`
`
`9/30/10
`
`Houda Mahayni, Ph.D.
`
`
`
`
`
`Elsbeth Chikhale, Ph.D.
`
`
`
`Elsbeth Chikhale, Ph.D.
`
`9/29/10
`
`Jessica Cole, Ph.D.
`
`6 6
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`The Chemistry Review for NDA 200-678
`
`
`
`
`The Executive Summary
`
` I. Recommendations
`
`A.
`Recommendation and Conclusion on Approvability
`
`From the CMC point of view, the application is recommended for APPROVAL.
`
`The provided stability data support a shelf life of 15 months for the blisters and
`21 months for the bottles, when stored at 20° to 25°C (68°-77°F); excursions
`permitted between 15 and 30°C (59 and 86°F) (see USP Controlled Room
`Temperature).
`
`
`Final labeling will be done in coordination with the clinical division.
`
`
`
`
`
`B.
`
`
`
`II.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`N/A
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product and Drug Substances
`1) Drug Product
`
`The proposed drug product is a fixed dose combination (FDC) of saxagliptin and
`metformin HCl. The proposed strengths are: saxagliptin 5 mg/metformin HCl
`500 mg, saxagliptin 5 mg/metformin HCl 1000 mg, saxagliptin 2.5
`mg/metformin HCl 1000 mg.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`.
`
`7 7
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`The total tablet weight is 1180 – 1653 mg. The commercial drug product will be
`manufactured at the BMS facility in Mount Vernon, IN.
`
` A
`
` Quality by Design (QbD) based approach was followed for development of the
`drug product. This approach was followed only for the
`. The QbD
`implementation approach was similar to what was followed for another approved
`product ONGLYZA from BMS, given the similarities between the two products.
`ONGLYZA was developed following the QbD paradigm and was a part of FDA’s
`CMC Pilot Program.
`
`Following the QbD paradigm, critical quality attributes (CQA) identified for this
`product were saxagliptin potency and CU (Content Uniformity). The applicant
`claimed that
`
` However, per the Biopharmaceutics review
`by Houda Mahayni, Ph.D., dated 9/27/10, this claim is not acceptable because
`
`. The
`applicant has included acceptable dissolution testing as part of the drug product
`specifications.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Manufacturing control strategy included the following components:
`
`8 8
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`
`The provided stability data do support a shelf life of 21 months when packaged in
`bottles
` and
`
`the stability data support the proposed shelf life of 15 months
` in blisters when stored at 20° to
`25°C (68°-77°F); excursions permitted between 15° to 30°C (59°-86°F) [see USP
`Controlled Room Temperature]. The drug product is not sensitive to light
`exposure. The proposed FDC drug product will be commercialized in high-
`density polyethylene (HDPE) bottles with a two-piece, child-resistant,
`continuous-thread closure having an aluminum-foil induction seal (inner seal).
`Larger bottles (e.g., pharmacy or institutional packages) have a one piece
`continuous-thread closure with an aluminum-foil induction seal (inner seal). The
`bottles contain activated carbon/silica gel desiccant packet(s). An additional
`package for the proposed drug product is a
` blister (physician samples).
`
`
`2) Drug Substance: Saxagliptin:
`
`The drug substance, saxagliptin, is a previously approved drug substance,
`produced by
` All information regarding the physicochemical
`properties, impurities, method of synthesis and purification, process controls,
`control of raw materials, container closure system and stability of saxagliptin are
`provided in NDA 22-350 for Onglyza® (saxagliptin) Tablets (from the same
`applicant as this NDA). NDA 22-350 was approved by FDA on 7/31/2009. The
`drug substance saxagliptin will be manufactured at the BMS facility in Sword,
`
`Ireland (same as for NDA 22-350). The retest period for saxagliptin is
`when stored at USP controlled cold temperature i.e. between 2° and 8°C (36° and
`46°F); excursions permitted between 0° and 15°C (32° and 59°F).
`
`Drug Substance: Metformin HCl:
`
`The drug substance, metformin HCl, is a previously approved drug substance,
`produced by chemical synthesis. All information regarding the physicochemical
`properties, impurities, method of synthesis and purification, process controls,
`control of raw materials, container closure system and stability of metformin HCl
`are provided in the Drug Master Files (DMFs)
` both held by
`. The drug substance is supplied as metformin HCl
`
`. DMF
` was reviewed on 11/13/2007 (review #4 by
`
`9 9
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
` was reviewed on
`Aloka Srinivasan, Ph.D.) and found adequate. DMF
`6/29/2010 (review #5 by Elsbeth Chikhale, Ph.D.) and found adequate in support
`of this NDA. The drug substance metformin HCl will be manufactured by
`. The retest period
`
`
` when stored in the
` at long term ICH room temperature
`
`
`
`for metformin hydrochloride is
`described in DMF
`conditions.
`
`B. Description of How the Drug Product is Intended to be Used
`
`
`
`
`
`The drug product is indicated as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes when treatment with both
`saxagliptin and metformin is appropriate. The maximum daily dose is 5 mg for
`saxagliptin and 2000 mg for metformin HCl.
`
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`From the CMC point of view, the application is recommended for APPROVAL.
`
`The provided stability data support a shelf life of 15 months for the blisters and
`21 months for the bottles, when stored at 20° to 25°C (68°-77°F); excursions
`permitted between 15 and 30°C (59 and 86°F) (see USP Controlled Room
`Temperature).
`
`
`
`.
`
`
` Final labeling will be done in coordination with the clinical division.
`
`
`III. Administrative
`
`A. Reviewer’s Signature: in DARRTS
`
`
`
`
`
`
`
`
`
`
`B. Endorsement Block: in DARRTS
`
`C. cc Block: in DARRTS
`
`10 10
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`72 Page(s) have been Withheld in
`Full as b4 (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/
`----------------------------------------------------
`
`ELSBETH G CHIKHALE
`09/30/2010
`
`ALI H AL HAKIM
`09/30/2010
`
`Reference ID: 2843829
`
`

`

`
`
`
`DATE: May 10, 2010
`
`TO: Saxagliptin/metformin HCl Fixed Dose Combination (FDC) tablets (NDA 200-678)
`Review Team
`
`FROM: Elsbeth Chikhale, Ph.D. (elsbeth.chikhale@fda.hhs.gov 301-796-1659) /
`Sharmista Chatterjee, Ph.D. (on behalf of the CMC review team)
`
`THROUGH: Christine Moore, Ph.D.
`
`SUBJECT: Consideration for Inspection (CFI) memo
`
`
`NDA 200-678 is submitted by Bristol-Myers Squibb Co. (BMS) for
`(saxagliptin/metformin HCl XR) tablets for oral administration, containing either
`5 mg/500 mg, 5 mg/1000 mg or 2.5 mg/1000 mg fixed dose combination (FDC) of
`saxagliptin/metformin HCl. Both drug substances are active ingredients of previously
`approved drug products. Saxagliptin is the active ingredient in Onglyza (saxagliptin)
`Tablets (NDA 22-350), and metformin is the active ingredient in Glycophage (metformin
`HCl) Tablets (NDA 20-357) and Extended release Glycophage XR (metformin HCl)
`Tablets (NDA 21-202). The proposed indication is for treatment of patients with type 2
`diabetes. The FDC drug product proposed in NDA 200-678 is designed to provide
`immediate release for saxagliptin and extended release for metformin HCl.
`
`
`
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`
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`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`2 Page(s) have been Withheld in Full as b4
`(CCI/TS) immediately following this page
`
`

`

`
`The CMC review team is willing to share their knowledge with the investigator prior
`to and during the inspection. If you have any questions, please email or call the
`primary CMC reviewer Elsbeth Chikhale, Ph.D. – 301-796-1659;
`elsbeth.chikhale@fda.hhs.gov
`
`(b) (4)
`
`

`

`Application
`Type/Number
`--------------------
`NDA-200678
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`BRISTOL MYERS
`SQUIBB
`
`------------------------------------------
` (saxagliptin +
`metformin XR) Tablets
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELSBETH G CHIKHALE
`05/24/2010
`
`ALI H AL HAKIM
`05/25/2010
`
`(b) (4)
`
`

`

`Initial Quality/CMC Assessment
`ONDQA
`
`Division of Metabolism and Endocrinology Products
`
`NDA: 200678
`Applicant: Bristol-Myers Squibb Co.
`Stamp Date: 29-DEC-2009
`PDUFA Date: 29-OCT-2010
`[none]
`Proposed Proprietary Name:
`Established Name: Saxagliptin/metformin hydrochloride
`Dosage form and strength: Tablet: immediate release saxagliptin and extended
`release metformin hydrochloride –
`5/500, 5/1000, 2.5/1000
`(mg/mg saxagliptin anhydrous free base/
`metformin hydrochloride)
`Route of Administration: oral
`Indications: Type 2 diabetes
`
`CMC Lead: Su (Suong) Tran, Branch II/DPA I/ONDQA
`
`ONDQA Fileability: Yes
`
`
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`Page 1 of 23
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`

`

`CDRH or CBER
`EA
`
`EES
`OSE
`Methods Validation
`
`Microbiology
`
`Pharm/Tox
`
`Initial Quality/CMC Assessment
`ONDQA
`
`
`COMMENT
`
`
`CONSULTS/ CMC
`RELATED REVIEWS
`Biopharmaceutics
`
`The ONDQA Biopharmaceutics Review Staff will review the
`biowaiver requests. Consult request was sent on 25-JAN-2010.
`Not Applicable
`The categorical exclusion claim will be assessed by Primary
`Reviewer.
`Compliance: “Acceptable” on 09-FEB-2010
`Labeling consult request will be sent as part of DMEP’s request.
`Validation may be requested of FDA labs after test methods are
`finalized.
`The proposed limit of
`microbial limits will be reviewed by the Microbiology team.
`May Not Be Applicable. Proposed limits on impurities are within
`applicable ICH qualification thresholds.
`This is an electronic NDA, filed as a 505(b)(1) application. The associated IND is IND 76500.
`
`Reference is made to the DMF
`approved NDA 20357, and approved NDA 21202 for all CMC information on the metformin HCl drug
`substance. This new NDA and the referenced NDAs have the same applicant: access to the CMC
`information in the referenced NDAs and their CMC reviews is permitted.
`Reference is made to the approved NDA 22-350 (saxagliptin) for all CMC information on the saxagliptin
`drug substance. This new NDA and the referenced NDA have the same applicant: access to the CMC
`information in the referenced NDA and its CMC reviews is permitted.
`
`The product is a fixed dose combination tablet available in the strength of 5/500, 5/1000, 2.5/1000
`(mg/mg saxagliptin anhydrous free base/metformin hydrochloride). The excipients are
`carboxymethylcellulose sodium, hypromellose 2208, magnesium stearate, polyvinyl alcohol,
`polyethylene glycol 3350, titanium dioxide, talc, and iron oxides. The 5/500 strength also has
`microcrystalline cellulose and hypromellose 2910. The tablet consists of the extended release metformin
` The product will be packaged in HDPE bottles
`with child-resistant closures and desiccant for commercial distribution, and blister packs as physician
`samples.
`Reference is also made to the approved NDA 22350 (saxagliptin), approved NDA 20357 (metformin
`HCl) and approved NDA 21202 (metformin HCl) for supporting CMC information on the drug product
`manufacturing and testing. This new NDA and the referenced NDAs have the same applicant.
`Maximum daily dose is 5 mg saxagliptin and 2000 mg metformin HCl.
`
`Page 2 of 23
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`Initial Quality/CMC Assessment
`ONDQA
`
`
`
`Has all information requested during the IND phases, and at the pre-NDA meetings been included?
`The NDA includes some information as requested by FDA during the IND development. There is no
`item-by-item response to FDA’s comments, which makes it difficult to assess in the limited time allotted
`for this filing memo/IQA whether the applicant has provided a satisfactory response to each question.
`The primary reviewer will assess the information in the NDA and decide whether issues previously
`raised have been satisfactorily addressed. The reviewer will also confirm that information previously
`agreed upon by FDA and the sponsor has not been changed in its final version in the NDA (for example,
`specifications, packaging systems, etc.)
`Major CMC issues discussed in the FDA letter dated 17-NOV-2009 include:
`o Agreement on the registration stability protocol
`o Omission of polymorph testing in the drug product specification
`Major issues discussed in the FDA letter dated 20-MAR-2009 include:
`
`
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`Page 3 of 23
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`(b) (4)
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`

`

`Initial Quality/CMC Assessment
`ONDQA
`
`Drug substance:
`
`
`Saxagliptin monohydrate:
`
`
`
`Metformin hydrochloride:
`
`
`
`
`
`
`
`
`
`
`Review comments:
`• Reference is made to the DMF
`, approved NDA 20357, and approved NDA 21202 for all CMC information on the
`metformin HCl drug substance. No issue should be found for metformin HCl because only the
`
`Page 4 of 23
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`(b) (4)
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`Initial Quality/CMC Assessment
`ONDQA
`
`approved information in NDA 20357 and NDA 21202, including the information in their
`supporting DMFs
`, will be referenced.
`• Reference is made to the approved NDA 22-350 (saxagliptin monohydrate) for all CMC
`information on the saxagliptin drug substance. This new NDA and the referenced NDA have the
`same applicant. No issue should be found for saxagliptin because only the approved information
`in NDA 22350 will be referenced.
`• The drug substance specifications are included in the NDA. The applicant states that the
`metformin HCl specification is the same as the approved specification in the referenced NDA
`20357. No such statement is given for the saxagliptin specification, and the reviewer will confirm
`that this specification is the same as the approved on in the referenced NDA 22350.
`
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`Page 5 of 23
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`(b) (4)
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`

`
`
`Initial Quality/CMC Assessment
`ONDQA
`
`
`Drug product
`
`The composition of the drug product is copied the following pages.
`
`Review comments:
`• Established name and dosage strength. The proposed established names of the product are
`“saxagliptin” and “metformin hydrochloride”, which are acceptable because they correlate with
`the dosage strengths as per current CDER policy on nomenclature. The dosage strength of
`saxagliptin is of the anhydrous free base. As discussed in the reviews of the referenced approved
`NDA 22350, the drug substance saxagliptin monohydrate
`
`. The reviewer will ensure that the full amount of the
`saxagliptin hydrochloride salt is included in the prescribing information and packaging labels,
`but it should not have the same prominence as the dosage strength.
`
`• Dosage form. The product is a fixed dose combination tablet available in the strength of 5/500,
`5/1000, 2.5/1000 (mg/mg saxagliptin anhydrous free base/metformin hydrochloride). Each tablet
`consists of
`
`
`
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`
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`Page 6 of 23
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`Initial Quality/CMC Assessment
`ONDQA
`
`• Quality control of excipients.
`
` is a degradant
`
`
`
`
`
`
`
`• Comparability of the product used in the clinical studies, stability studies, and commercial
`product.
`
`
`
`o 5/500 dosage strength: Product batch 7L24093 was used in the pivotal study CV181060
`to show BE between the 5/500 tablet to the co-administered 5 mg saxagliptin and 500 mg
`metformin HCl approved products. The only formulation difference between batch
`7L24093 and the commercial product is in the color and print. This batch had a yellow
`coat vs. the commercial butterscotch color coat, and this batch did not have any code
`printing. The color and printing difference should not affect the performance of the
`product. Primary stability batches have the same formulation as the commercial product,
`as confirmed by the applicant in the 25-JAN-2010 amendment.
`
`o 5/1000 dosage strength: Product batch 8E43429/8C4324Z was used in the pivotal study
`CV181076 to show BE between the 5/1000 tablet to the co-administered 5 mg
`saxagliptin and 1000 mg metformin HCl products. The only formulation difference
`between batch 8E43429/8C4324Z and the commercial product is in the print. This batch
`did not have any code printing. The printing difference should not affect the performance
`of the product. Primary stability batches have the same formulation as the commercial
`product, as confirmed by the applicant in the 25-JAN-2010 amendment.
`
`Page 7 of 23
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`Initial Quality/CMC Assessment
`ONDQA
`
`CHEMISTRY NDA FILEABILITY CHECKLIST
`
`Comment
`
`No
`
`
`
`
`
`
`Exclusion request per 21 CFR
`25.31 is included.
`By reference to DMFs.
`
`
`
`Requested information may be in
`different locations in NDA.
`
`
`
`
`Not applicable.
`
`
`IS THE CMC SECTION OF APPLICATION FILEABLE? YES
`The following parameters are necessary in order to initiate a full review, i.e., complete enough to review
`but may have deficiencies.
`Content Parameter
`Is the section legible, organized, indexed, and paginated adequately?
`Are ALL of the manufacturing and testing sites (including contract
`sites) identified with full street addresses (and CFNs, if applicable)?
`Is a statement provided to indicate whether each manufacturing or
`testing site is ready for inspection or, if not, when it will be ready?
`Is a statement on the Environmental Impact provided as required in
`21 CFR 314.50(d)(1)(iii)?
`Is information on the Drug Substance provided as required in 21
`CFR 314.50(d)(1)(i)?
`Is information on the Drug Product provided as required in 21 CFR
`314.50(d)(1)(ii)?
`If applicable, has all information requested during the IND phases
`and at the pre-NDA meetings been included?
`Have draft container labels and package insert been provided?
`Have all DMF References been identified?
`Is information on the investigational formulations included?
`Is information on the methods validation included?
`If applicable, is documentation on the sterilization process validation
`included?
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`Yes
`x
`x
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`x
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`x
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`x
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`x
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`x
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`x
`x
`x
`x
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`Page 23 of 23
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`(b) (4)
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`15 Page(s) have been Withheld in Full as
`b4 (CCI/TS) immediately following this
`page
`
`

`

`Application
`Type/Number
`--------------------
`NDA-200678
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`BRISTOL MYERS
`SQUIBB
`
`----------------------