`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`206073Orig1s000
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT" EVALUATISZEN REQUEST
`SUMMARY REPORT
`
`Application:
`
`0'
`
`"ode:
`
`Stamp Date:
`
`PDUFA Date:
`
`Action Goal:
`
`NDA 206073/000
`
`510
`
`4
`
`30-JAN-2014
`
`30-JAN-2015
`
`District Goal:
`
`30—AUG—2014
`
`Sponsor:
`
`BOEHRIN-IE ER INGELHEIM
`
`900 RIDGEBURY RD
`
`RIDGEFIELD, CT 06877
`
`Brand Name:
`
`Estab. Name:
`
`EMPAGLIFLOZIN AND LINAGLIPTIN TABLETS
`
`EMPAGLIFLOZIN AND LINAGLIPTIN TABLETS
`
`Generic Name:
`
`LINAGLIPTIN
`
`Produz‘t “inner-2r- Dosage Form; Ingredient; Strengths
`00* ‘ TABLET; LINAGLIPTIN; 5MG
`OUT; TABLET; EMPAGLIFLOZIN; TOMG
`002; TABLET; LINAGLIPTIN; SMG
`CCE; TABLET; EMPAGLIFLC' KIN; EZEMG
`
`FDA Contacts:
`
`J. LEGINUS
`
`E. PFEILER
`
`P. KUMAR
`
`Prod Qua! Reviewer
`
`Micro Reviewer
`
`Product Quality PM
`
`C. CAPPEL—LYNCH
`Regulatory Project Mgr
`
`
`(HFD-8101
`
`(HF-22)
`
`(HFD-BOJ)
`
`3017964102
`
`3017960642
`
`240023722
`
`321 1’338436
`
`
`Overall Recommendation:
`ACCEPTABLE
`on 22‘JUL—2014
`by R. SAFAAI-JAZI
`
`
`()
`
`3017964463
`
`Establishment:
`
`CFN:
`
`9610492
`
`FEI:
`
`3002306556
`
`BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG
`BINGER STREET 173
`
`INGELHEIM AM RHEIN, RHEINLAND—PFALZ, GERMANY
`
`DMF No:
`
`AADA:
`
`'msibilities:
`
`FINISHED DOSAGE MANUFACTURER
`
`a:
`
`TABLETS, PROMPT RELEASE
`
`0:11 Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`OC RECOMMENDATION
`
`10-JUN-2014
`
`ACCEPTABLE
`
`Reason:
`DISTRICT RECOMMENDATION
`
`
`Establishment:
`
`_.__...._._:F_EE___1..5.;6_6.é.6_.__._.._ __M____. ,.-L_.__..____._,.
`1510690
`CFN:
`BOEHRINGER INGELHEIM ROXANE INC
`
`DMF No:
`
`:‘LLW‘A.
`
`COLUMBUS, , UNITED STATES 432289579
`
`Responsibilities:
`
`FINISHED DOSAGE LABELER
`
`FINISHED DOSAGE PACKAGER
`
`Profile:
`
`TABLETS, PROMPT RELEASE
`
`UAI .oéatus:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`OC RECOMMENDATION
`
`12~FEB—2014
`
`ACCEPTABLE
`
`Reason:
`BASED ON PROFILE
`
`
`January 21, 2015 6:44 AM
`
`FDA Confidential - Internal Distribtriion Only
`
`Page 1 of 3
`
`Reference ID: 3699635
`Reference ID: 3699635
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`DMF No:
`
`
`
`AADA:
`
`Responsibilities:
`
`f-‘NSHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Lasl Milestone:
`
`Milestone Me:
`
`Decision:
`
`QC RECOMMENDATION
`
`.LE-FEB-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`Reason:
`
`Establishment:
`CFN:
`
`FEl: -—
`
`DlilF No:
`
`
`
`AADA:
`
`Responsibilities:
`
`”INISHED DOSAGE CT HER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`0A! Status:
`
`NONE
`
`Last Milestong:
`
`Milestone Date:
`
`Decision:
`
`OC RECOMMENDATION
`
`25-FEB-2014
`
`ACCEPTABLE
`
`Reason:
`DISTRICT RECOMMENDATION
`
`
`
`
`Establishment:
`
`cm: m_——FEI.—
`
`DMF No:
`
`
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAl Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`OC RECOMMENDATION
`
`'- 2~FEB-2014
`
`ACCEPTABLE
`
`Reason:
`BASED ON PROFILE
`
`
`January 21, 2015 6:44 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 2 of 3
`
`Reference ID: 3699635
`
`

`

`FEE}: CDEER ILL-"it;
`
`ESTABLISHMENT EVALUAT i;L-3f=I REQUEST
`SUMMARY REFCIE
`
`Eslabllshment:
`
`DMF No:
`
`Responsibilities:
`
`
`
`AADA:
`
`FINISHED DOSAGE LABELER
`FINISHED DOSAGE PACKAGER
`
`Profile:
`
`TABLETS, PROMPT HIE—ELSE
`
`JAI 713.115.
`
`NONE
`
`Last Mllestone:
`
`Milestone Date:
`
`Declslon:
`
`Reason:
`
`OC RECOMMENDATION
`
`22-JUL-2014
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`Establishment:
`
`
`
`DMF No:
`
`ITIAL: .-
`
`Responslbllltles:
`
`FINISHED DOSAGE LABELER
`FINISHED DOSAGE PACKAGER
`
`Profile:
`
`TABLETS, PROMPT RELEASE
`
`0A! fiaiatus:
`
`NONE
`
`mum“;
`
`oc RECOMMENDATION
`
`"meddle Date:
`
`12-FEB-2014
`
`Decision:
`
`Reason:
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`January 21, 2016 6:44 AM
`
`FDA Confidentei - Internal Die .:'E..'
`
`. vi Ln OnIy
`
`Page 3 of 3
`
`Reference ID: 3699635
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`MARY GRACE LUBAO
`02/09/2015
`
`Reference ID: 3699635
`
`

`

`
`
`Chemistry Review Data Sheet
`
`NDA 206073
`
`Glyxambi®
`(Empagliflozin/Linagliptin) Tablet
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`Joseph Leginus, PhD
`Office of New Drug Quality Assessment
`Division III, Branch VII
`
`For the Division of
`
`Metabolism and Endocrinology Products
`
`CHEMISTRY REVIEW #1
`
`Reference ID: 3612777
`
`Page 1 of 69
`
`

`

`
`
`Chemistry Review Data Sheet
`
`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 ............................................................ 9
`
`111. Administrative......................................................................................................................... 11
`
`A. Reviewer’s Signature: in DAARTS. .............................................................................................. 11
`
`B. Endorsement Block: in DAARTS ................................................................................................... 11
`
`C. CC Block:
`
`in DAARTS. ............................................................................................................. 11
`
`Chemistry Assessment ........................................................................................... 12
`
`1. Review of Common Technical Document-Quality (Ctd—Q) Module 3.2: Body of Data .......... 12
`
`S DRUG SUBSTANCES .................................................................................................................. 12
`
`P DRUG PRODUCT ........................................................................................................................ 19
`
`A APPENDICES ............................................................................................................................... 59
`
`R REGIONAL INFORMATION ...................................................................................................... 59
`
`II. Review of Common Technical Document-Quality (Ctd—Q) Module 1 ...................................60
`
`A. Labeling & Package Insert ............................................................................................................. 60
`
`B. Environmental Assessment or Claim of Categorical Exclusion .................................................... 67
`
`Reference ID: 361 2777
`
`Page 2 of 69
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`Document Date
`
`Document Date
`
`30-Jan-2014
`
`24-Jun-2014
`
`1. NDA 206073
`
`2
`
`. REVIEW #2 1
`
`3 4
`
`. REVIEW DATE: 19-Aug-2014
`
`. REVIEWER: Joseph Leginus, PhD
`
`5 . PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`N/A
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; 3 1 Reviewed
`Original NDA
`Amendment
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`Boehringer Ingelheim Pharmaceuticals, Inc
`
`900 Ridgebury Road, PO Box 368
`Ridgefield, CT 06877
`Chung Lee-Sogaard
`Associate Director, Regulatory Affairs
`
`203-798-4224
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Glyxambi
`b) Non-Proprietary Name CNN): Empagliflozin/Linagliptin
`c) Code Name/# (ONDC only): Empagliflozin/Linagliptin Fihn—coated Tablets
`Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 4 (New combination)
`
`0 Submission Priority: Standard
`
`9. LEGAL BASIS FOR SUBMISSION: This NDA is submitted as a 505(b)(1)
`application.
`
`Reference ID: 361 2777
`
`Page 3 of 69
`
`

`

`
`
`Chemistry Review Data Sheet
`
`10. PHARMACOL. CATEGORY:
`
`Empagliflozin is an inhibitor of the sodium—dependent glucose cotransporter 2 (SGLT-Z),
`the major transporter responsible for renal glucose reabsorption; Linagliptin is an
`inhibitor of the enzyme dipeptidyl peptidase 4 (DPP—4) for use in the treatment of type 2
`diabetes mellitus.
`
`ll. DOSAGE FORM: Immediate release tablet Gilm—Coated)
`
`12. STRENGTH/POTENCY:
`
`Empagliflozin/Linagliptin tablets are manufactured in two strengths: 10 mg/5 mg and 25
`mg/5 mg represented as empagliflozin mg/linagliptin mg.
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. RX/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS {SPECIAL PRODUCTS ON-LINE TRACKlNG SYSTEM):
`
`
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`A. Empagliflozin
`Chemical Name: D—Glucitol, l ,S—anhydro-l-C-[4—chloro—3-[[4—[[(3S)—tetrahydro—3—
`furanyl]oxy]phenyl]methyl]phenyl]-, (l S)
`Structural Formula:
`
`
`
`Molecular Formula: C23H27C107
`
`Molecular Weight: 450.91 g/mol
`
`Reference ID: 3612777
`
`Page 4 of 69
`
`

`

`
`
`Chemistry Review Data Sheet
`
`B. Linagliptin
`Chemical Name: 8-[(3R)—3-aminopiperidin— l -yl]-7—but—2-yn— l —yl—3—methyl- 1 - [(4-
`methquuinazolin-2-yl)methyl]-3 ,7-dihydro— 1 H-purine— 2,6—dione.
`Structural Formula:
`
`0
`//CH3
`©:’/N )\ I N%N
`
`O
`
`CH3
`
`N
`
`t|3H3
`
`"”2
`
`Molecular Formula: C25H28N802
`Molecular Weight: 472 gig/mo]
`Chirality: One chiral center (R conformation).
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`3
`Date Review
`
`Com leted Item Referenced
`
`Stan's
`
`
`
`
`
`
`
`
`
`Action codes for DMF Table:
`l — DIVIF 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")
`
`Reference ID: 3612777
`
`Page 5 of 69
`
`

`

`
`
`Chemistry Review Data Sheet
`
`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:
`
`”—
`
`
`
`Applicant]Sponsor is Boehringer Ingelheim
`
`18. STATUS:
`
`ONDC:
`CONSULTS/ CMC
`
`EES
`
`Pharm/Tox
`
`recommendation of
`Accetable has been rovided.
`
`22-Jul-2014
`
`N/A
`
`below ICH qualification
`thresholds.
`
`.
`
`Biopharmaceutics evaluation
`
`.
`
`.
`
`.
`
`Joseph Leginus
`
`Methods Validation
`
`N°t quurred_ N0 novel
`methods.
`
`EA
`
`Microbiology
`
`Conducted by CMC reviewer.
`Granting the categorical
`exclusion as per 21 CFR
`25.31 0
`
`Recommended for approval
`from the standpoint of product
`uuali microbiolo 3 .
`
`19-Aug-2014
`
`8-Aug—2014
`
`Erika Pfeiler
`
`l9. ORDER OF REVIEW: N/A
`
`Reference ID: 361 2777
`
`Page 6 of 69
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 206073
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The recommendation from a CMC perspective is Approval, pending:
`
`A recommendation from Biophannaceutics regarding adequacy of dissolution
`testing of the drug product, currently pending.
`
`B.
`
`Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`Not applicable.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`DRUG SUBSTANCES
`
`Glyxambi is a combination product containing two drug substances: empagliflozin and
`linagliptin.
`
`Empagliflozin
`Empagliflozin (an NME) is described in NDA 204629 for empagliflozin tablets which
`received a Complete Response on 3/4/2014. This was due to a Withhold recommendation
`from the Office of Compliance following an inspection at the Boehringer Ingelheim
`Pharma GmbH & Co KG, Ingelheim am Rhein, Germany drug substance/drug product
`manufacturing plant. NDA 204629 was approved on Aug 1, 2014 after an overall cGMP
`recommendation was made by the Office of Compliance upon resubmission of the NDA.
`Information for empagliflozin is provided in the sponsor’s NDA 204629 and is
`incorporated by reference herein.
`
`Reference ID: 361 2777
`
`Page 7 of 69
`
`

`

`
`
`Executive Summary Section
`
`Linagliptin
`The drug substance linagliptin is described in NDA 201280 for Tradj enta® (linagliptin)
`tablet which was approved on May 2, 2011. Information for linagliptin is provided in the
`Applicant’s approved NDA 201280 and is incorporated by reference herein.
`
`DRUG PRODUCT
`
`Glyxambi (empagliflozin/linagliptin) tablet is formulated as a fixed-dose combination,
`immediate—release, film—coated tablet for oral administration containing two drug
`substances, empagliflozin and linagliptin. Two dosage strengths have been developed
`containing two levels of empagliflozin (10 mg or 25 mg) and a fixed amount of
`linagliptin (5 mg). The two tablets are identical in shape (arc triangular, flat faced, bevel-
`edged fihn—coated tablets) but are distinguished by color and debossing. The 10 mg/5 mg
`tablets are pale yellow and one side is debossed with "10/5" while the 25 mg/5 mg tablets
`are pale pink and one side is debossed with "25/5". Total weight for each strength tablet
`is 185 mg.
`
`The two strength tablets are formulated with the same excipients in slightly differing
`amounts. Excipients including mannitol, pregelatinized starch, corn starch, copovidone,
`crospovidone, magnesium stearate and talc are part of the tablet core. The film coat is
`based on
`(m4) Yellow (10 mg/5 mg) and
`mm) (25 mg/5 mg) mixtures
`which consist of hypromellose (m4), mannitol, titanium dioxide, talc, polyethylene glycol
`m4) and ferric oxide yellow and red, respectively. No novel excipients are used to
`manufacture empagliflozin/linagliptin tablets. All excipients have compendial references
`and are identified in FDA's Inactive Ingredients Database as inactive ingredients found in
`other oral tablet products at levels higher than those described above for
`empagliflozin/linagliptin tablets.
`
`Empagliflozin/linagliptin tablets are manufactured
`
`mu)
`
`Tablets are packaged in a) high density
`polyethylene plastic bottles (60 cc and 375 cc) containing 30, 90 or 1000 tablets, and b)
`aluminum—
`(m4) blisters containing 10 tablets.
`
`The proposed release specifications include description (visual), identification (HPLC
`and UV), degradation products fl—IPLC), assay GIPLC), content uniformity,
`disintegration, and microbiological quality. Batch analysis data from 8 clinical and
`stability lots manufactured at commercial scale at the proposed site for commercial
`production show that the drug products meet the specifications proposed.
`
`Results from stability studies show that empagliflozin/linagliptin tablets packaged in
`either HDPE bottles or blister packs remain stable through a) 12 months at the long-term
`storage condition of 25°C/60% RH, and b) 6 months at the accelerated condition of
`40°C/75% RH. The drug product also demonstrates good stability when exposed to
`
`Reference ID: 361 2777
`
`Page 8 of 69
`
`

`

`
`
`Executive Summary Section
`
`ambient and high humidity conditions for longer than the in-use period. Photostability
`studies indicate no effect on the product due to exposure to light. Based on these data,
`and following the recommendations outlined in ICH QEl Evaluation of Stability Data, a
`shelf-life of 24 months is gamed for empagliflozin/linagliptin tablets 10 mng mg and 25
`ng5 mg when maintained at 25°C/60% relative humidig in the proposed container
`closure systems. This is in agreement with the Applicant’s proposed expiry period for the
`drug product.
`
`Boehringer Ingelheim requested a categorical exclusion from submitting an
`environmental assessment for the drug product empagliflozin/linagliptin tablets based on
`the regulations in 21 CFR, part 25, section 25.31(b). The request is granted.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Glyxambi combines two antihyperglycemic agents (empagliflozin and linagliptin) with
`complementary mechanisms of action to improve glycemic control in patients with type 2
`diabetes.
`
`Empagliflozin is an inhibitor of the sodium-dependent glucose cotransporter 2 (SGLT—Z).
`SGLT—2 accounts for about 90 percent of glucose reabsorption into the blood. Therefore,
`an SGLT-2 inhibitor such as empagliflozin may be effective at reducing blood glucose
`levels by blocking glucose reabsorption in the kidney and allowing glucose to be excreted
`in the urine.
`
`Linagliptin is an orally-active inhibitor of DPP-4, an enzyme that degrades the incretin
`hormones glucagon-like peptide-l (GLP—1) and glucose-dependent insulinotropic
`polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin
`hormones, stimulating the release of insulin in a glucose-dependent manner and
`decreasing the levels of glucagon in the circulation.
`
`Empagliflozin/linagliptin is formulated as an immediate-release tablet for once-daily oral
`administration. The recommended starting dose is 10 mg/5 mg. The dose may be
`increased to 25 mg/5 mg in patients who require additional glycemic control.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`This is a 505(b)(1) application where one of the two drug substances, empagliflozin, is a
`New Molecular Entity (NME). Information for the drug substances, empagliflozin and
`linagliptin are provided in the Applicant’s NDA 204629 for Empagliflozin tablets
`(recommended for approval from a CMC perspective) and their approved NDA 201280
`for Tradjenta® (linagliptin) tablets, respectively.
`
`The drug product will be manufactured as immediate-release tablets at the Boehringer
`Ingelheim Pharma facility in Ingelheim am Rhein, Germany. Drug product specifications
`include attributes standard for this type of dosage form. Limits on degradation products
`
`Reference ID: 3612777
`
`Page 9 of 69
`
`

`

` CHENIISTRY REVIEW
`
`Executive Smmnary Section
`
`are within applicable ICH thresholds. Eight clinical and stability lots have been
`manufactured at commercial scale at the proposed site for commercial production with
`each lot meeting the specifications proposed. Stability of the drug product has been
`adequately established in the two container closure systems, HDPE bottles and blister
`packs to grant a shelf-life of 24 months when stored at controlled room temperature.
`
`The risk from a safety perspective for this combination drug product is anticipated to be
`low since each drug substance in empagliflozin/linagliptin is an active ingredient in two
`of the Applicant’s previously submitted drug products at similar strengths: NDA 204629
`for Empagliflozin tablets (recommended for approval from a CMC perspective) and the
`approved NDA 201280 for Tradjenta® (linagliptin) tablets, respectively.
`
`ONDQA Risk Assessment
`
`From Initial Quali Assessment
`Product
`
`Risk
`Factors That Can
`Impact the CQA Ranking*
`
`Risk Mitigation
`Approach
`
`Risk
`Evaluation
`
`Lifecycle
`Considerations/
`
`Comments**
`
`Attribute/
`
`CQA
`
`Assay,
`Stability
`
`Physical
`Stability
`(solid state)
`
`
`
`. Formulation
`0 Container
`
`Closure
`
`0 Raw Materials
`. Process
`
`0 Parameters
`
`o Scale/Equipment
`o Slte
`
`o Formulation
`
`0 Container
`
`Closure
`
`. Raw Materials
`
`0 Process
`
`. Parameters
`
`o Scale/Equipment
`0 SI“?
`
`0 Formulation
`
`0 Container
`
`Closure
`
`0 Raw Materials
`
`. Process
`
`0 Parameters
`
`o Scale/Equipment
`. Site
`
`Acceptable
`
`Linagliptin-
`related Single
`Impurity > 33%
`
`Empagliflozin-
`and Linagliptin-
`related
`
`impurities in
`accordance with
`
`the ICH
`
`Q3B(R2)-
`
`Empagliflozin —
`no polymorphs.
`
`Linagliptin —
`two polymorphs.
`(b) (4)
`
`Acceptable
`
`l' Acceptable 1
`
`Microbial
`
`Limits
`
`SeeRi_kAssessment—ythe Microbiology reviewer.
`
`Reference ID: 361 2777
`
`Page 10 of 69
`
`

`

`
`
`Executive Summary Section
`
`See Risk Assessment by the Biopharmaceutics reviewer. Other
`
`CQAs
`
`*Risk ranking applies to product attribute/CQA
`**For example, post marketing commitment, knowledge management post approval, etc.
`
`Acceptable cGMP recommendations have been received from the Office of Compliance
`for all manufacturing and testing facilities. An Overall Compliance recommendation of
`Acceptable was provided on 22-Jul-2014.
`
`A recommendation for approval from the standpoint of product quality microbiology was
`provided on 08-Aug-2014.
`
`At this time, recommendations from Biopharmaceutics regarding adequacy of dissolution
`testing of the drug product.
`
`III. Administrative
`
`A. Reviewer’s Signature: in DAARTS.
`
`B. Endorsement Block: in DAARTS.
`
`C. CC Block: in DAARTS.
`
`58 Page(s) has been Withheld in Full as b4 (CCIITS) immediately following this page
`
`Reference ID: 3612777
`
`Page 11 of 69
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOSEPH LEGINUS
`08/19/2014
`
`DANAE D CHRISTODOULOU
`08/19/2014
`I concur with the reviewer's conclusions and recommendation
`
`Reference ID: 3612777
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`IQA and Filing Review Cover Sheet
`
`1. NEW DRUG APPLICATION NUMBER: 206073
`
`2. DATES AND GOALS:
`
`Letter Date: 29—JAN-2014
`PDUFA Goal Date: 30-JAN-2015
`
`3. PRODUCT PROPERTIES:
`
`Submission Received Date : 30—JAN—2014
`
`Trade or Proprietary Name:
`Established Name (USAN):
`
`Not yet finalized
`E n a ‘ iflozin/lina (1i tin
`
`
`
`Route of Administration _
`10/5 and 25/5 m,
`Rx/OTC Dis ensed _
`4.
`INDICATION. Treatment of type 2 diabetes
`
`5. DRUG SUBSTANCE STRUCTURAL FORMULA:
`
`Empagli ozin
`D-Glucitol, 1 .5-anhydro-l -C-[4-chloro-3-[[4-[[(3 S)-tetrahydro-3-fi1ranyl]oxy]phenyl]methyl]phenyl]-. (1 S)
`C23H27C107
`450.91 g/mol
`
`
`
`Linagliptin
`1H-Purine-2.6-dione. 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-1-yl)-3.7-dihydro-3-methyl-l-[(4-methyl-
`2-quinazolinyl)methyl]-
`C25H28N802
`
`472.54 g/mol
`
`6. NAME OF APPLICANT (as indicated on Form 356h): Boehringer Ingelheim
`
`7. SUBMISSION PROPERTIES:
`
`(select one) _tandard
`Review Priori
`Submission Classification
`
`Breakthrou- n Thera _o
`
`(Chemical Classification Code)
`Application Type _05(b)(1)
`
`Page 1 of 15
`
`Reference ID: 3473661
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`
`For new NDAs
`
`Division of Metabolism and Endocrinology Products
`CMC Lead: Suong (Su) Tran
`
`
`
`Responsible Organization
`(Clinical Division)
`8. CONSULTS:
`CONSULT
`Biometrics
`Clinical Pharmacology
`Establishment Evaluation
`Request (EER)
`x
`
`Pharmacology/Toxicology
`Impurity degradants are below ICH qualification thresholds.
`
`
`Methods Validation
`To be determined by Primary Reviewer
`x
`
`Environmental Assessment
`Categorical exclusion request to be reviewed by Primary
`Reviewer
`x
`
`CDRH
`
`Does the submission contain any of the following elements? No
`Nanotechnology
`QbD Elements
`PET
`
`YES NO
`
`x
`
`x
`x
`
`
`COMMENTS:
`
`
`
`To be sent by ONDQA-PM
`
`
`Is a team review
`recommended?
`
`Other, please explain
`
`Yes - One CMC reviewer and one Biopharmaceutics reviewer are needed
`to review the drug product information of the new NDA. Reference is
`made to the approved NDA 201280 (linagliptin) and the pending NDA
`204629 (empagliflozin) for all CMC information on the drug substances.
`
`
`
`Overall Filing Conclusions and Recommendations
`
`CMC:
`Is the Product Quality Section of the application fileable from a CMC perspective? Yes
`Are there potential CMC review issues to be forwarded to the Applicant with the 74-Day
`letter? No
`
`
`Biopharmaceutics: See the Biopharmaceutics filing review attached at the end of this IQA.
`
`Is the Product Quality Section of the application fileable from a Biopharmaceutics
`perspective? Yes
`Are there potential Biopharmaceutics review issues to be forwarded to the Applicant with
`the 74-Day letter? Yes
`1. Provide supportive validation data for the dissolution method (i.e., method robustness,
`etc.) and analytical method (precision, accuracy, linearity, stability, etc.).
`2. Submit SAS Transport files of the pharmacokinetic data from the BE study. The data
`should include AUC0-t, AUC0-inf, Cmax, Tmax, Kel, and T1/2 as shown. Please submit
`the data in the following format:
`
`SUBJ SEQ PER TRT AUCT AUCI CMAX TMAX KE Thalf
`
` Microbiology: See Microbiology Filing Review in DARRTS for details and for any potential
`Page 2 of 15
`
`
`Microbiology review issues.
`
`
`Reference ID: 3473661
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`Summary of Critical Issues and Complexities
`
`Previous quality-related meeting between ONDQA and the sponsor:
`Comments from FDA’s letter dated 14-AUG-2013:
`
`Does the Division have any comments about the proposed approach for Module 3 and Q08 of
`the empagliflozin + linagliptin F DC NDA?
`
`FDA Pre-Meeting Response
`
`We agree with your proposed Module 3 sections and QOS of the new NDA. We remind you to
`include in the NDA a complete list of all testing and manufacturing facilities used for the drug
`substances and drug product in Form 356h of the NDA, with detailed contact information and a
`statement that all facilities are ready for the GMP inspection at the time of the NDA submission.
`
`Mimi
`
`The single entity tablets empagliflozin and linagliptin that were used in the pivotal safety and
`efficacy Study 1275.1 and the relative bioavailability Study 1275.3 are equivalent formulations
`to the to-be-marketed empagliflozin 10 and 25 mg tablets described in NDA 204629 (submitted
`March 5, 2013) and to the marketed TRADJENTA 5 mg tablets described in NDA 201280
`(approved May 2, 201 1). At the start of study 1275.1, the empagliflozin + linagliptin FDC
`tablets in Study 1275.1 were
`m’to the empagliflozin . linagliptin FDC tablets used in the
`bioavailability Study 1275.3, which supports equivalence of the FDC to its components. During
`the 1275.1 trial. there was a minor change to the arrantitative. commsitinn of the. FDC tahleremw
`
`(”min the FDC tablets when compared to the FDC tablets used in
`1275.3 and first used in trial 1275.1. This change was not deemed to impact the bioavailability
`of the active components. Considering these data. Bl believes that reference to the NDAs for
`the individual drug products to support safety and efficacy of empagliflozin and linagliptin is
`appropriate. Does the Division concur with 31’s approach?
`
`FDA Pre-Meeting Resmnse
`
`Biggharmaceutics:
`
`This submission did not include a comparative qualitative and quantitative composition of the
`FDC formulation for the pre- and post change. However, based on the percent change
`mentioned in the question above, this manufacturing change could be considered minor requiring
`dissolution profiles comparisons. Therefore, to support the bridging of these formulations,
`provide the following information in the NDA submission:
`
`1. Comparative qualitative and quantitative composition of the FDC formulation for both
`strengths of your product for the pre- and post change.
`
`2. Comparative dissolution data using the regulatory dissolution method for each FDC
`tablet strength manufactured pre- and post- the proposed changes. Also, provide
`individual (n=12), mean, minimum, maximum, RSD, profile data, and calculate the
`similarity factor f2 values.
`
`Page 3 of 15
`
`Reference ID: 3473661
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`
`For new NDAs
`
`
`
`
`
`
`
`
`
`Reference ID: 3473661
`
`Page 4 of 15
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`
`For new NDAs
`
`
`
`
`
`Page 5 of 15
`
`
`
`
`
`
`
`Reference ID: 3473661
`
`

`

`0NDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`Drug Substance
`
`The drug substance empagliflozin is described in NDA 204629 (submitted March 5, 2013)
`for empagliflozin film-coated tablets. which is currently under review. The drug substance
`linagliptin is described in NDA 201280 for linagliptin film-coated tablets. for which
`marketing authorization was granted (approved May 2. 2011). Both drug substances are
`therefore not covered in Module 3 for empagliflozin/ linagliptin film-coated tablets or in this
`Quality Overall Surmnary.
`
`Drug Product
`The film-coated tablets consist of immediate release empagliflozin and immediate release
`linagliptin with the strengths of 10/5 and 25/5 mg/mg (empagliflozin/linagliptin).
`
`Composition. (see the copied co
`exci ient. Ma
`
`esium stearate
`
`sition table at the end of this review) There is no novel
`
`Comparability of the product used in the clinical studies, stabilifl studies, and commercial
`product. Product batches 108244 (10/5 mg/mg) and 108247 (25/5 mg/mg) were used in the
`pivotal clinical study 1275.1. These batches have the commercial formulation and were
`manufactured at the commercial site/scale, packaged in the commercial container/closure
`systems. They are submitted as primary stability batches in the NDA.
`
`Product manufacture.
`
`Drug product spgcification. (see the copied specification at the end of this review)
`The drug product specification includes attributes standard for this type of dosage form
`Limits on degradation products are within applicable ICH thresholds. Only two degradants are
`found above the ICH reporting threshold during the stress and primary stability studies (copied
`below). Limits on both degradants are within applicable ICH qualification thresholds.
`-s the major degradation product of the active ingredient linagliptin observed in
`‘ ozin/ lina
`' tin film-coated tablets. This ' m is derived fi'om linagliptin by
`structure is shown in Fieure
`
`
`
`
`Page 6 of 15
`
`Reference ID: 3473661
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`(b) (4)
`is the major degradation product of the active ingredient empagliflozin (heated in
`empatzliflozin n linatzliptin film-coated tablets. This impun‘tv is the
`(b) ‘4)
`mmrhe structure IS shown in
`
`name 1 l.
`
`(b) (4)
`
`All dissolution-related infomlation. including disintegration. will be evaluated by the ONDQA
`Biopharmaceutics team. Of the several attributes omitted from the drug product specification.
`these two specific omissions will be evaluated by the reviewer:
`M“) (claimed by the
`applicant not to be a Critical Quality Attribute because it
`"m"
`, and enantiomeric purity (claimed by the applicant to undergo no change during
`stress stability of the product).
`
`Container closure systems. The drug product will be packaged in HDPE bottles and aluminum
`blisters. The applicant states that the safety of the product-contact packaging components is
`shown by compliance to the indirect food additives. Applicable USP testing per <671> for water
`vapor transmission was conducted. Compatibility is shown by stability data supporting both
`packaging systems. The reviewer will review information in the NDA and DMFs per internal
`policy on the review of container closure systems for solid oral dosage form drug products.
`
`Stabilifl. Sufiicient stability data are provided in the submission for filing. The primary reviewer
`will determine the final expiry based on all available data and per ICH QlE Evaluation of
`Stability Data. For the six product batches (3 of each strength) manufactured by the commercial
`process/site/scale: Stability data are provided for 12 months at 25 °C/60% RH. and 30 °C/75%
`RH and for 6 months at 40 °C/75% RH. Additional data are provided for the stress studies (heat,
`humidity. and photostability).
`
`Comparabilifl protocol. None proposed.
`
`FILING REVIEW CHECKLIST
`
`The following parameters are necessary in order to initiate a fill] review. i.e.. complete enough to
`review but may have deficiencies. On initial overview of the NDA application for filing:
`
`A. GENERAL
`
`'
`
`
`
`__
`1
`Is the CMC section organized
`adequately?
`Is the CMC section indexed and
`
`....... ll—ad- a uatel ?
`—ll—'
`
`section legible?
`
`Page 7 of 15
`
`Reference ID: 3473661
`
`

`

`
`
`4.
`
`
`
`*
`
`
`
`5.
`
`6.
`
`
`
`7.
`
`ONDQA Initial Quality Assessment (IQA) and Filing Review
`
`For new NDAs
`
`Has all information requested
`during the IND phase, and at the
`
`pre-NDA meetings been
`included?
`
`x
`
`
`
`
`
`x
`
`x
`
`
`
`
`
`
`
`
`
`B. FACILITIES*
`If any information regarding the facilities is omitted, this should be addressed ASAP with the
`applicant and