`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`201280Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`

`

`
`NDA 201280
`
`CMC Director Review
`
`Tradjenta*
`(Linagliptin) Tablets
`*This proposed name has not yet been finalized in negotiations between the Agency and Boehringer
`Ingelheim.
`
`Summary of the Basis for the Recommended Action
` from Chemistry, Manufacturing, and Controls
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`
`
`
`
`Applicant: Boehringer Ingelheim Pharmaceuticals, Inc.
`900 Ridgebury Road
`PO Box 368
`Ridgefield, CT 06877
`
`Indication: Adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes.
`
`
`Presentation: The proposed market packages for the 5 mg tablets are 60 cc HDPE
`bottles containing 30 or 90 tablets and 375 cc HDPE bottles
`containing 1,000 tablets (intended for dispensing at mail order
`pharmacies). All of the bottles are equipped with a child resistant,
`senior friendly closure with an induction foil seal liner, and a silica
`gel desiccant packet.
`
`
`Establishments Evaluation Report (EER) Status:
`
`Consults:
`
`
`
`
`
`
`EA –
`
`
`Statistics –
`Methods Validation –
`Biopharm–
`
`
`
`Acceptable
`N/A
`Acceptable
`Acceptable
`
`Acceptable
`
`Reference ID: 2917882
`
`

`

`NDA 201-280
`
`Summary Basis of Recommended Action – CMC
`
`P. 2
`
`
`Microbiology –
`Pharm Toxicology –
`
`N/A
`Acceptable
`
`July 02, 2010
`N/A
`None at this time.
`
`
`
`
`
`Original Submission:
`
`
`Re-submissions:
`
`Post-Approval CMC Agreements:
`
`Drug Substance
`The drug substance, linagliptin, is a new molecular entity manufactured through
`a series of chemical synthetic steps, by Boehringer Ingelheim Pharma GmbH &
`Co. KG in Germany, and the relevant CMC issues related to the manufacture of
`this material are described in the Drug Substance section of the Chemistry
`Assessment. Linagliptin is a crystalline white to yellowish solid, which has been
`found to exist
`
`
`
`
`
`
`
`
`. Boehringer Ingelheim classifies this drug substance
`as a Class III compound according to the Biopharmaceutical Classification
`System (BCS) because of its high solubility and low bioavailability. Linagliptin
`shows high solubility (> 1 mg/ml) in aqueous media up to pH 8. Adequate drug
`substance specifications were provided which included acceptance criteria for
`Appearance, Identification, Melting Temperature, Organic Impurities, Organic
`Volatile Impurities, Enantiomeric Purity, Residual Solvents, Water Content,
` Assay, and Particle Size Distribution.
`The NDA contains satisfactory stability data to support a retest date of
`for the drug substance for storage at 25°C/60 % R.H.
`
`Drug substance is satisfactory
`
`
`
`
`Reference ID: 2917882
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 201-280
`
`Summary Basis of Recommended Action – CMC
`
`P. 3
`
`Drug product
`The drug product, with the proposed the proprietary name TRADJENTA and the
`established name Linagliptin, is a dipeptidyl peptidase-4 inhibitor indicated as
`an adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes.
`The manufacturing process of linagliptin film-coated tablets is a standard process
`
`
`
`
`
`
`
`
`The dosage form is a 5.0 mg immediate release film-coated tablet that
`is light red, round, biconvex, bevel-edged with one side debossed with the
`Boehringer Ingelheim company symbol and the other side debossed with ‘D5’.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` An adequate drug product specification was provided which
`included acceptance criteria for the Description of the dosage form, Identification
`of the active ingredient, Loss on Drying, Dissolution, Uniformity of Dosage
`Units, Assay, and Degradation Products. The proposed market packages for the
`5 mg tablets are 60 cc HDPE bottles containing 30 or 90 tablets and 375 cc HDPE
`bottles containing 1,000 tablets.
`Besides linagliptin, the drug product contains the following inactive ingredients:
`Mannitol, pregelatinized starch, corn starch, copovidone, and magnesium
`stearate. In addition, the film coating contains the following inactive ingredients:
`hypromellose, titanium dioxide, talc, polyethylene glycol, and red ferric oxide.
`All of the inactive ingredients are compendial.
`Drug product is satisfactory
`
`Overall Conclusion: From CMC point of view, the NDA is recommended for
`approval.
`
`
`Eric P Duffy, Ph.D.
`Director, Division III
`ONDQA/CDER/FDA
`
`
`Reference ID: 2917882
`
`1 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ERIC P DUFFY
`03/14/2011
`
`Reference ID: 2917882
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
` NDA 201-280
`
`
` Tradjenta*
` (Linagliptin) Tablets
`*This proposed name has not yet been finalized in negotiations between the Agency and Boehringer Ingelheim.
`
`
`
`
`Boehringer Ingelheim Pharmaceuticals, Inc
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Sheldon Markofsky, Ph.D.
`
`
` and
` Olen Stephens, Ph.D.
` [For sections P.2, P.3, and P.4]
`
` Division of Metabolism and Endocrine Products (HFD-510)
`
` and
`
`
`
`
`
`
`
`
`
`Office of New Drug Quality Assessment III
`
`
`Branch VII
`
`
`
`
`n201280RevNumber2B.doc
`
`
`Reference ID: 2914317
`
`1
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`Table of Contents.......................................................................................2
`Chemistry Review Data Sheet...................................................................3
`The Executive Summary............................................................................7
`
`I.
`
`II.
`
`Recommendations................................................................................................ 7
`Recommendation and Conclusion on Approvability......................................................7
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable ........................................................................7
`
`A.
`B.
`
`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 ...........................................8
`C. Basis for Approvability or Not-Approval Recommendation................................................9
`
`III. Administrative............................................................................................................ 9
`A. Reviewer’s Signature.........................................................................................................9
`B. Endorsement Block............................................................................................................9
`C. CC Block............................................................................................................................9
`Chemistry Assessment .................................................Starting on pp. 10
`
`I
`
`S
`P
`A
`R
`
` DRUG SUBSTANCE............................................................................................pp. 10
` DRUG PRODUCT ...............................................................................................pp. 17
` APPENDICES (Attachments).....................................................................................34
` REGIONAL INFORMATION.......................................................................................34
`
`List Of Deficiencies To Be Communicated ......................................................... 38
`
`II.
`
`
`
`Reference ID: 2914317
`
`2
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`
`1. NDA 201-280
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: 07-March- 2011
`
`4. REVIEWER: Sheldon Markofsky, Ph.D.
`
`
`5. PREVIOUS DOCUMENTS:
`Previous Documents
`NDA (Original)
`Filing Review Document
`Amendment
`IR Letter
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`Submission(s) Reviewed
`NDA Original
`Amendmenta
`Amendmentb
`Amendmentc
`
`Document Date
`02-July-2010
`08-Aug-2010
`23-Sept.-2010
`08-Dec-2010
`
`Document Date
`02-July-2010
`06-Jan-2011
`27-Jan-2011
`01-Feb-2011
`
`.
`a) The 1-6-11 amendment provides a number of responses to our IR Letter of 12-8-2010.
`b) The 1-27-11 amendment provides the additional responses to our IR Letter of 12-8-2010.
`c) The 2-1-11 amendment provides up-dated container related labels.
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`Address:
`
`Name: Boehringer Ingelheim Pharmaceuticals, Inc.
`900 Ridgebury Road
`PO Box 368
`Ridgefield, CT 06877
`
`Maureen Oakes, Associate Director, DRA
`Telephone: 203-798-5723
`
`Representative:
`
`
`
`
`
`
`
`Reference ID: 2914317
`
`Page 3 of 38
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`a) Proprietary Name: TRADJENTA (This proposed name has not yet been finalized in negotiations
`between the Agency and Boehringer Ingelheim.)
`b) Non-Proprietary Name: Linagliptin tablets
`c) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type:1
`• Submission Priority: S
`
` 9. LEGAL BASIS FOR SUBMISSION: 505(b) (1)
`
`10. PHARMACOL. CATEGORY: Treatment of type 2 diabetes mellitus
`
`11. DOSAGE FORM: Tablets
`
`12. STRENGTH/POTENCY: 5 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED: X Rx ___OT
`
`
` 15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`
`
`
` SPOTS product – Form Completed
`
` X Not a SPOTS product
`
`
`
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`
`
`
`
`
`
`C25H28N8O2
`472.54 g/mol.
`
`INN: Linagliptin
`USAN: Linagliptin
`
`
`
`
`Reference ID: 2914317
`
`Page 4 of 38
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`
`Chemical names:
`
`(Chemical Abstracts)
`1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7- (2-butyn-1-yl)-3,7-dihydro-3
`methyl-1-[(4-methyl-2- quinazolinyl)methyl]-
`
`(IUPAC) and (INN)
`8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-yn-1-yl-3-methyl-1- [(4-methylquinazolin-2
`yl)methyl]-3,7-dihydro-1H-purine- 2,6-dione
`
`CAS Registry Number 668270-12-0
`Company Code Number BI 1356 BS
`
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`
`
`
`DMF
`#
`
`TYP
`E
`
`HOLDER
`
`ITEM
`REFERENCED CODE1 STATUS2
`
`III
`
`III
`
`III
`
`III
`
`3
`
`3
`
`4
`
`3
`
`DATE
`REVIEW
`COMPLETED
`9-15-00 and
`9-23-05
`
`COMMENTS
`
`Reviewed by
`Don Klein
`
`Adequate
`
`Adequate
`
`3-24-10
`
`Adequate
`
`
`
`Adequate
`
`9-27-00
`
`Reviewed by R.
`Agarwal
`See Chemistry
`Review #1 of
`this NDA.
`Reviewed by
`R. Lostritto
`
`
`
`
`
`Chemistry Review Data Sheet
`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`3 – Reviewed previously and no revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other (explain under "Comments")
`
` 2
`
` Adequate, Inadequate, or N/A (There is enough data in the application, therefore the
`DMF did not need to be reviewed)
`
`
`
`
`
`
`Reference ID: 2914317
`
`Page 5 of 38
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`B. Other Documents:
`
`DOCUMENT
`
`APPLICATION NUMBER
`70,963
`
`DESCRIPTION
`IND for Linagliptin
`
`
`
`
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`IND
`
`
`18. STATUS:
`
`
`
`
`ONDC:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Acceptable
`EES
`Acceptable
`Pharm/Tox
`Methods Validation Acceptable
`EA
`Acceptable
`Microbiology
`N/A
`ONDQA Dissolution
`Acceptable
`Review
`
`
`19. ORDER OF REVIEW: N/A (OGD Only)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`8-9-10
`3-6-11
`12-30-10
`12-30-10
`
`2-28-11
`
`
`David Carlson
`S. B. Markofsky
`S. B. Markofsky
`
`Sandra Suarez)-Sharp
`
`
`
`Reference ID: 2914317
`
`Page 6 of 38
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The Executive Summary
`
`The Chemistry Review for NDA 201-280
`
` I.
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From a Chemistry, Manufacturing, and Controls (CMC) point of
`view, this NDA can be approved,
`
`[Labeling will be finalized at a later date as part of the review team's labeling negotiation.]
`
`
`II.
`
`
`B. Recommendation on Phase 4 (Post-Marketing)
`Commitments, Agreements, and/or Risk Management Steps, if
`Approvable
`
`None
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product and Drug Substances
`
`1) Drug Product
`
`The drug product, with the proposed the proprietary name TRADJENTA and the
`established name Linagliptin, is a dipeptidyl peptidase-4 inhibitor indicated as an
`adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes. The dosage form is a 5.0 mg immediate release film-coated tablet that
`is light red, round, biconvex, bevel-edged with one side debossed with the
`Boehringer Ingelheim company symbol and the other side debossed with ‘D5’.
`
` An adequate drug product specification was provided which included
`acceptance criteria for the Description of the dosage form, Identification of the
`active ingredient, Loss on Drying, dissolution, Uniformity of Dosage Units, Assay,
`and Degradation Products. The proposed market packages for the 5 mg tablets
`are 60 cc HDPE bottles containing 30 or 90 tablets and 375 cc HDPE bottles
`containing 1,000 tablets (intended for dispensing at mail order pharmacies). All
`
`Reference ID: 2914317
`
`Page 7 of 38
`
`(b) (4)
`
`(b) (4)
`
`

`

`8
`
`
`
`of the bottles are equipped with a child resistant, senior friendly closure with an
`induction foil seal liner, and silica gel desiccant packets. Physician samples are
`aluminum/aluminum push-through blisters containing 7 tablets.
`
`Besides linagliptin, the drug product contains the following inactive ingredients:
`Mannitol, pregelatinized starch, corn starch, copovidone, and magnesium
`stearate. In addition, the film coating contains the following inactive ingredients:
`hypromellose, titanium dioxide, talc, polyethylene glycol, and red ferric oxide. All
`of the inactive ingredients are compendial.
`
`
`
`2) Drug Substance
`
`
`The drug substance, linagliptin, is manufactured by Boehringer Ingelheim
`Pharma GmbH & Co. KG in Germany, and the relevant CMC issues related to
`the manufacture of this material are described in the Drug Substance section of
`the Chemistry Assessment. Linagliptin is a crystalline white to yellowish solid,
`which has been found to exist
`
`
`
`
` Boehringer Ingelheim
`classifies this drug substance as a Class III compound according to the
`Biopharmaceutical Classification System (BCS) because of its high solubility and
`low bioavailability. In this connection, linagliptin shows high solubility (> 1 mg/ml)
`in aqueous media up to pH 8. An adequate drug substance specification was
`provided which included acceptance criteria for Appearance, Identification,
`Melting Temperature, Organic Impurities, Organic Volatile Impurities,
` Assay, and
`Enantiomeric Purity, Residual Solvents, Water Content,
`Particle Size, Satisfactory stability data was provided to support a retest date of
` for the drug substance for storage at 25°C/60 % R.H.
`
`
`From a Chemistry, Manufacturing, and Controls (CMC) point of view, the drug
`substance can be deemed acceptable.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The recommended (and maximum) dose of TRADJENTA, for the Treatment of
`type 2 diabetes mellitus, is one 5 mg tablet once daily, without regard to foods.
`The stability studies support an expiration-dating period of 30 months for
`TRADJENTA 5 mg tablets when stored at controlled room temperature [25°C
`(77°F)], with excursions permitted between 15°C and 30°C packaged in all of the
`proposed commercial container closure systems. Consequently, a 30 month
`expiry is granted.
`
`
`
`
`
`Reference ID: 2914317
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`From a Chemistry, Manufacturing, and Controls (CMC) point of view, this NDA
`can be approved on the following basis:
`
`
`• Adequate information was provided in the NDA for the synthesis,
`purification and controls of the drug substance
`
`9
`
`• Adequate manufacturing information to support the proposed to-be-
`marketed drug product
`
`• Adequate specifications and controls for the drug product
`
`• Satisfactory methods to support lot release and stability monitoring of the
`drug product
`
`• Adequate stability package to support the recommended expiry period of
`the drug product
`
`• An acceptable Establishment Inspection Report for the relevant facilities
`employed for the manufacture and testing of the drug substance and the
`drug product
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` [Labeling will be finalized at a later date as part of the review team's labeling negotiation.]
`
`
`III. Administrative
`
`A. Reviewer’s Signatures
`
``
`
`Sheldon Markofsky, Ph.D. (Chemistry Reviewer)
`Olen Stephens, Ph.D. (Chemistry Reviewer)
`
`B. Endorsement Block (OGD only)
`
`
`N/A
`
`
`
`C. CC Block (OGD only)
`N/A
`
`Reference ID: 2914317
`
`29 Page(s) has 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/
`----------------------------------------------------
`
`SHELDON B MARKOFSKY
`03/07/2011
`
`ALI H AL HAKIM
`03/07/2011
`
`Reference ID: 2914317
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
` NDA 201-280
`
`
` Tarjenta*
` (Linagliptin) Tablets
`* Boehringer Ingelheim has not yet finalized (selected) this proposed name.
`
`
`
`Boehringer Ingelheim Pharmaceuticals, Inc
`
` Sheldon Markofsky, Ph.D.
`
`
` and
` Olen Stephens, Ph.D.
`[For sections P.2, P.3, and P.4 related to Quality by Design (QBD)]
`
`
` Division of Metabolism and Endocrine Products (HFD-510)
`
` and
`
`
`
`
`
`
`
`
`
`Office of New Drug Quality Assessment III
`
`
`Branch VII
`
`
`
`
`
`File: 201280Rev2
`
`
`Reference ID: 2899744
`
`1
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`Table of Contents.......................................................................................2
`Chemistry Review Data Sheet...................................................................3
`The Executive Summary............................................................................7
`
`I.
`
`II.
`
`Recommendations................................................................................................ 7
`Recommendation and Conclusion on Approvability......................................................7
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable ........................................................................7
`
`A.
`B.
`
`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 ...........................................8
`C. Basis for Approvability or Not-Approval Recommendation................................................8
`
`III. Administrative............................................................................................................ 9
`A. Reviewer’s Signature.........................................................................................................9
`B. Endorsement Block............................................................................................................9
`C. CC Block............................................................................................................................9
`Chemistry Assessment .................................................Starting on pp. 10
`
`I
`
`S
`P
`A
`R
`
` DRUG SUBSTANCE............................................................................................pp. 10
` DRUG PRODUCT .............................................................................................pp. 114
` APPENDICES (Attachments)...................................................................................191
` REGIONAL INFORMATION.....................................................................................N/A
`
`List Of Deficiencies To Be Communicated ....................................................... 193
`
`II.
`
`
`
`Reference ID: 2899744
`
`2
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
` Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`
`1. NDA 201-280
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 30-December- 2010
`
`4. REVIEWER: Sheldon Markofsky, Ph.D.
`
`
`5. PREVIOUS DOCUMENTS:
`Previous Documents
`NDA (Original)
`Filing Review Document
`Amendment
`IR Letter
`
`Document Date
`02-July-2010
`08-Aug-2010
`23-Sept.-2010
`07-Dec-2010
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`Document Date
`Submission(s) Reviewed
`02-July-2010
`NDA Original
`Amendmenta
`23-Sept.-2010
`Amendmentb
`06-Jan-2011
`a) The 9-23-10 amendment provides up-dated packaging information.
`b) The 1-6-11 amendment provides a number of responses to our IR Letter of 12-7-2010.
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`Address:
`
`Name: Boehringer Ingelheim Pharmaceuticals, Inc.
`900 Ridgebury Road
`PO Box 368
`Ridgefield, CT 06877
`
`Maureen Oakes, Associate Director, DRA
`Telephone: 203-798-5723
`
`Representative:
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`a) Proprietary Name: TARJENTA (The applicant has not yet finalized (selected) this proposed name.)
`b) Non-Proprietary Name: Linagliptin tablets
`c) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type:1
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`Reference ID: 2899744
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`Page 3 of 205
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`• Submission Priority: S
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` 9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
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`10. PHARMACOL. CATEGORY: Treatment of type 2 diabetes mellitus
`
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`11. DOSAGE FORM: Tablets
`
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`12. STRENGTH/POTENCY: 5 mg
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`13. ROUTE OF ADMINISTRATION: Oral
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`14. Rx/OTC DISPENSED: X Rx ___OT
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` 15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
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`
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` SPOTS product – Form Completed
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` X Not a SPOTS product
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`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`
`
`
`
`
`
`C25H28N8O2
`472.54 g/mol.
`
`INN: Linagliptin
`USAN: Linagliptin
`
`Chemical names:
`
`(Chemical Abstracts)
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`Reference ID: 2899744
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`1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7- (2-butyn-1-yl)-3,7-dihydro-3
`methyl-1-[(4-methyl-2- quinazolinyl)methyl]-
`
`(IUPAC) and (INN)
`8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-yn-1-yl-3-methyl-1- [(4-methylquinazolin-2
`yl)methyl]-3,7-dihydro-1H-purine- 2,6-dione
`
`CAS Registry Number 668270-12-0
`Company Code Number BI 1356 BS
`
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`
`DMF
`#
`
`TYP
`E
`
`HOLDER
`
`ITEM
`REFERENCED CODE1 STATUS2
`
`DATE
`REVIEW
`COMPLETED
`9-15-00 and
`9-23-05
`
`COMMENTS
`
`Reviewed by
`Don Klein
`
`Adequate
`
`Adequate
`
`3-24-10
`
`Reviewed by R.
`Agarwal
`
`Adequate
`
`
`
`
`
`Adequate 9-27-00
`
`Reviewed by
`R. Lostritto
`
`
`
`
`
`III
`
`III
`
`III
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`III
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`Chemistry Review Data Sheet
`
`
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`3
`
`3
`
`4
`
`3
`
`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`3 – Reviewed previously and no revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other (explain under "Comments")
`
` 2
`
` Adequate, Inadequate, or N/A (There is enough data in the application, therefore the
`DMF did not need to be reviewed)
`
`Reference ID: 2899744
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`Page 5 of 205
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`(b) (4)
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`(b) (4)
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`B. Other Documents:
`
`DOCUMENT
`
`APPLICATION NUMBER
`70,963
`
`DESCRIPTION
`IND for Linagliptin
`
`
`
`
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`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`IND
`
`
`18. STATUS:
`
`
`
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`ONDC:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Acceptable
`EES
`Pending
`Pharm/Tox
`Methods Validation Acceptable
`EA
`Acceptable
`Microbiology
`N/A
`ONDQA Dissolution
`Acceptable
`Review
`
`
`19. ORDER OF REVIEW: N/A (OGD Only)
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`8-9-10
`
`12-30-10
`12-30-10
`
`Not yet
`finalized
`
`
`David Carlson
`S. B. Markofsky
`S. B. Markofsky
`
`Sandra Suarez)-Sharp
`
`
`
`Reference ID: 2899744
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`CHEMISTRY REVIEW
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`II.
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`The Executive Summary
`
`The Chemistry Review for NDA 201-280
`
` I.
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From a Chemistry, Manufacturing, and Controls (CMC) point of
`view, this NDA can be approved, pending acceptable responses to
`our information Request, dated 12-8-2010.
`
`
`B. Recommendation on Phase 4 (Post-Marketing)
`Commitments, Agreements, and/or Risk Management Steps, if
`Approvable
`
`None
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product and Drug Substances
`
`1) Drug Product
`
`The drug product, with the proposed the proprietary name TARJENTA and the
`established name Linagliptin, is a dipeptidyl peptidase-4 inhibitor indicated as an
`adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes. The dosage form is a 5.0 mg immediate release film-coated tablet that
`is light red, round, biconvex, bevel-edged with one side debossed with the
`Boehringer Ingelheim company symbol and the other side debossed with ‘D5’.
`
`
`
` The proposed market packages for the 5 mg tablets are 60 cc HDPE
`bottles containing 30 or 90 tablets and 375 cc HDPE bottles containing 1,000
`tablets (intended for dispensing at mail order pharmacies). All of the bottles are
`equipped with a child resistant, senior friendly closure with an induction foil seal
`liner, and silica gel desiccant packets. Physician samples are
`aluminum/aluminum push-through blisters containing 7 tablets.
`
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`Reference ID: 2899744
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`Page 7 of 205
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`(b) (4)
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`Besides linagliptin, the drug product contains the following inactive ingredients:
`Mannitol, pregelatinized starch, corn starch, copovidone, and magnesium
`stearate. In addition, the film coating contains the following inactive ingredients:
`hypromellose, titanium dioxide, talc, polyethylene glycol, and red ferric oxide. All
`of the inactive ingredients are compendial.
`
`
`
`8
`
`2) Drug Substance
`
`
`The drug substance, linagliptin, is manufactured by Boehringer Ingelheim
`Pharma GmbH & Co. KG in Germany, and the relevant CMC issues related to
`the manufacture of this material are described in the Drug Substance section of
`the Chemistry Assessment. Linagliptin is a crystalline white to yellowish solid,
`which has been found to exist
`
`
`
`
` Boehringer Ingelheim
`classifies this drug substance as a Class III compound according to the
`Biopharmaceutical Classification System (BCS) because of its high solubility and
`low bioavailability. In this connection, linagliptin shows high solubility (> 1 mg/ml)
`in aqueous media up to pH 8. Satisfactory stability data was provided to support
`a retest date of
` for the drug substance for storage at 25°C/60 % R.H.
`
`From a Chemistry, Manufacturing, and Controls (CMC) point of view, the drug
`substance can be deemed acceptable pending adequate responses to our
`information Request, dated 12-8-2010. We anticipate that the outstanding CMC
`issues can be readily resolved.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The recommended (and maximum) dose of TARJENTA, for the Treatment of
`type 2 diabetes mellitus, is one 5 mg tablet once daily, without regard to foods.
`The stability studies support an expiration-dating period of 30 months for
`TARJENTA 5 mg tablets when stored at controlled room temperature [25°C
`(77°F)], with excursions permitted between 15°C and 30°C packaged in all of the
`proposed commercial container closure systems. Consequently, a 30 month
`expiry is granted.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`From a Chemistry, Manufacturing, and Controls (CMC) point of view, this NDA is
`approvable at this time pending adequate responses to our Information Request
`
`
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`Reference ID: 2899744
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`(b) (4)
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`(b) (4)
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`
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`Letter. We anticipate that the outstanding CMC issues can be readily resolved.
`
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`9
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`III. Administrative
`
`A. Reviewer’s Signatures
`
``
`
`Sheldon Markofsky, Ph.D. (Chemistry Reviewer)
`Olen Stephens, Ph.D. (Chemistry Reviewer)
`
`B. Endorsement Block (OGD only)
`
`
`N/A
`
`
`
`C. CC Block (OGD only)
`N/A
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`Reference ID: 2899744
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`196 Pages 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/
`----------------------------------------------------
`
`SHELDON B MARKOFSKY
`02/02/2011
`
`ALI H AL HAKIM
`02/02/2011
`
`Reference ID: 2899744
`
`

`

`Initial Quality/CMC Assessment
`ONDQA
`
`Division of Metabolism and Endocrinology Products
`
`NDA: 201280
`Applicant: Boehringer Ingelheim Pharmaceuticals Inc.
`Stamp Date: 02-JUL-2010
`PDUFA Date: 02-MAY-2011
`Proposed Proprietary Name: Ondero
`linagliptin
`Established Name:
`Dosage form and strength:
`Immediate release tablet –
`5 mg
`Route of Administration: oral
`Indications: Treatment of type 2 diabetes
`
`CMC Lead: Su (Suong) Tran, ONDQA
`
`ONDQA Fileability: Yes
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`Page 1 of 29
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`CONSULTS/ CMC
`RELATED REVIEWS
`CBER
`CDRH
`Compliance (DMPQ)
`EA
`
`Methods Validation
`
`Microbiology
`OBP
`ONDQA Biopharm
`
`OSE
`Pharm/Tox
`
`QbD
`
`
`
`
`
`Initial Quality/CMC Assessment
`ONDQA
`
`
`COMMENT
`
`Not applicable
`Not applicable
`EER was sent to Compliance by ONDQA PM on 11-JUL-2010.
`The categorical exclusion claim will be assessed by Primary
`Reviewer.
`Validation may be requested of FDA labs after test methods are
`finalized.
`Not applicable
`Not applicable
`Review of all dissolution/drug release-related information.
`Assignment: S. Suarez Sharp as of 07-JUL-2010.
`Labeling consult request will be sent as part of DMEP’s request.
`Review of qualification information in support of limits on impurities
`in the drug substance.
`The application includes information on DoEs in support of the
`manufacturing design space (the ONDQA IO was notified on 07-JUL-
`2010).
`
`This is a 505(b)(1) application. The associated IND is IND 70963.
`The drug substance linagliptin is a New Molecular Entity (NME) and a small synthetic compound. It
`is xanthine-derived and an inhibitor of the dipeptidyl peptidase-4 enzyme. The structure has the R
`configuration at the chiral carbon of the 3-aminopiperidine group.
`The drug product is a 5 mg immediate-release tablet. The inactive ingredients are: mannitol,
`pregelatinized starch, corn starch, copovidone and magnesium stearate. In addition, the film coating
`contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol
`and red ferric oxide. The commercial packaging consists of bottles of 30-count, 90-count, and 1000-
`count. A physician sample will be available as a 7-count blister card. The product is stored at room
`temperature.
`
`Maximum daily dose is 5 mg linagliptin.
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`Page 2 of 29
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`Initial Quality/CMC Assessment
`OND