CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 2 -3 4 1
`
`CHEMISTRY REVIEWg S!
`
`

`

`MEMORANDUM
`
`Date: 04-Aug-2009
`
`From: Joseph Leginus, Review'Chemist, Branch II/DPA I/ONDQA
`
`To: NDA 22-341 Victoza® (liraglutide (rDNA origin) injection)
`
`Subject: Single, multi-dose (1.2 mg/1.8 mg) injector pen
`
`Background: ‘
`o On December 19, 2009, Novo Nordisk submitted an amendment to NDA 22-341
`describing an alternate pen configuration that would allow patients to use a single pen
`to inject each of the recommended doses (0.6, 1.2, 1.8 mg) of Victoza (liraglutide
`rDNA) injection). A——-—.—“————-————————‘\
`kf—wx—x
`~ _
`
`0
`
`b(é;
`
`uz'
`
`Reviewer’s Comments:
`0
`
`53(4)
`
`WW
`v
`
`9"“ . The draft labeling is the same as the previously submitted labeling with the
`additional pen configuration included.
`0 Dose accuracy study data was provided showing acceptable performance of the new
`pen at the three dose levels (0.6, 1.2, 1.8 mg).
`
`V o
`
`
`
`. [2(4)
`
`Conclusion:
`
`There are no CMC issues related to Novo Nordisk’s alternate pen configuration for
`Victoza, a single, multi-dose (1.2 mg/1.8 mg) pen.
`
`

`

`Submission
`Linked Applications Type/Number
`
`Sponsor Name
`
`Drug Name / Subject
`
`NDA 22341
`
`ORIG 1
`
`VICTOZA (LIRAGLUTIDE)
`
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`JOSEPH M LEGiNUS
`
`08/04/2009
`
`ALi H AL HAKIM
`
`08/04/2009
`
`

`

`Victoza®
`
`Liraglutide Injection
`NDA 22—341
`
`Summary of the Basis for the Recommended Action
`from Chemistry, Manufacturing, and Controls
`
`Applicant:
`
`Novo Nordisk, Inc.
`
`100 College Road West,
`Princeton, NJ 08540
`
`Indication:
`
`Liraglutide is indicated as an adjunct to diet and exercise to achieve
`glycemic control in patients with type 2 diabetes mellitus
`
`Presentation: Liraglutide injection is a parenteral drug product for once daily
`subcutaneous self-administration. It is supplied in multiple-dose pre-filled
`pen-injectors containing 3 mL of drug product at a concentration of 6
`
` >
`'
`o
`mg/mL. Luff—*-
`
`//————« ,
`
`11(4)
`
`EER Status:
`
`Acceptable, 23-Mar—2009
`
`Consults:
`
`EA — Categorical exclusion granted -
`CDRH - Completed, S. Syad, 13-Feb-2009
`Methods Validation — Revalidation by Agency was not requested
`Microbiology — Acceptable, B. Riley, 4-Mar-2009
`
`Original Submission: 23-May-2008
`
`Re—submissions: N/A
`
`Post-Approval CMC Agreements: None beyond the typical stability commitments.
`
`Drug Substance:
`
`Liraglutide is a fragment of the naturally occurring human GLP—l (Glucagon-like
`peptide-1) sequence position 7-37 having two modifications: 1) substitution of the
`naturally occurring lysine amino acid residue in position 34 by arginine, and 2)
`addition of a glutamic acid—spaced palmitic acid to the e-amino group of
`lysine in position 26. Liraglutide precursor is produced using recombinant DNA
`technology in yeast (Saccharomyces cerevisiae). The chemical name of liraglutide is
`
`

`

`NDA 22-341
`
`Summary Basis of Recommended Action — CMC
`
`p. 2
`
`glycine, L-histidyl-L-alany]-L-0L-glutamylglycyl-Lthreonyl-L-phenylalanyl-L—
`threonyl-L—seryl-L-0t-aspartyl-L-valyl-L-seryl~L-seryl-L-tyrosyl-L-leucyl-L-0L-
`glutam yl glycyl-Lglutaminyl-L-alanyl-L-alanyl-N6—[N-(l -oxohexadecyl)-L-y—
`glutamyl]—L-lysyl-L-0L-glutamyl-Lphenylalanyl-L-isoleucyl-L—alanyl-L-tryptophyl-L-
`leucyl-L-valyl-L~arginylglycyl—L—arginyl-. The chemical structure, molecular formula
`and molecular weight are provided below:
`
`H 0'.
`l0
`'7
`rigid—HiHun-(lamly-TEV—Hnfi‘hrfiw—Asp—VnlHSw—Ser—fia-[nu-Giu—Giyflin—AE a—Asan
`
`37
`M
`GEwfie—lle—Ala—Trp—LN-Vai-Arg-Ob’-Arg—Gly—COOl-i
`
`I Lysz'5
`Glu-spacer I
`
`NH
`
`O
`
`Palmitic acid.
`The molecular formula of liraglutide is CmHmsNuOg] with a molecular weight of 3751.20.
`
`HOQCANH
`
`O
`
`Liraglutide precursor is produced by recombinant DNA technology form yeast
`Saccharomyces cerevisiae. The manufacturing process is a ’ step process divided
`into three sections, fermentation, recovery, and purification. The purification process
`consists of purification of the liraglutide precursor, acylation of this precursorK
`, and finally purification ———_—_ of liraglutide.
`
`[3(4)
`
`The structure of liraglutide was elucidated by a variety of analytical and
`spectrophotometric techniques, including amino acid analysis (AAA), amino acid
`sequencing, mass spectrometry (MALDI-TOF MS), circular dichroism (CD) and
`peptide mapping.
`
`The proposed release specifications include appearance, identification (peptide
`mapping and HPLC), content (HPLC), specific bioactivity (CAMP assay), individual
`peptide related impurities and total peptide related impurities (HPLC), \—
`bacterial endotoxin, total viable count and host cell protein (ELISA). The proposed
`regulatory methods have been validated.
`
`Reference standards for the API have been developed and characterized. Product
`related impurities structurally related to liraglutide generated during the fermentation,
`recovery, purification or storage of the drug substance have classified based on their
`RP-HPLC elution position relative to the drug substance. Process derived impurities
`originating from the liraglutide manufacturing process were not detected in the drug
`substance. A shelf life of 24 months will be granted for the drug substance when
`stored at —l 8°C i2°C/ambient RH or lower temperatures based on real-time studies
`obtained from primary stability data.
`
`

`

`NDA 22-34]
`
`Summary Basis of Recommended Action — CMC
`
`p. 3
`
`Conclusion: The drug substance is acceptable.
`
`Drug Product:
`
`The drug product consists of an aqueous formulation at pH 8.15 of “‘— liraglutide
`
`with 0.14% disodium phosphate dihydrate
`, 1.4% propylene
`
`
`phenol
`glycol -————-————-—---~ and
`
`fl_.._————-
`. It is supplied in multiple-dose pre-filled pen-injectors ,_
`
`
`b
`(4)
`
`// m4;
`
`3‘4}
`
`The release specifications include appearance, identification (HPLC), content
`
`(HPLC), pH,
`-
`_
`related impurities and -,
`g
`_
`related impurities
`(HPLC), bacterial endotoxin, sterility, phenol content, particulate matter, freezing
`point depression (osmolality) and dose accuracy. A close correlation has been
`demonstrated between biological activity of liraglutide and content by HPLC under
`both normal and stressed conditions for the drug product. As a result, it has been
`determined that the HPLC assay is able to offer a reliable indication of the biological
`activity of liraglutide in the drug product. Therefore, bioactivity is not included in the
`proposed drug product specification.
`
`No new impurities were found in the drug product compared to the drug substance.
`The secondary packaging (pen-injector) adequately protects the drug product from
`degradation due to light. Review of the data for the primary stability batches through
`24 months of real time stability at 2 ~ 8°C show that the liraglutide 6.0 mg/mL drug
`product remains within the shelf life specification limits during this time. Satisfactory
`in—use Stability evaluation was performed for 32 days at 28 - 32°C using drug product
`batches. As a result, an expiry of 24 months at 2 — 8 °C plus 32 days at 28 — 32 °C is
`granted for the drug product.
`
`Conclusion: The drug. product is satisfactory.
`
`Overall Conclusion: From a CMC perspective, the application is recommended for
`approval.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Christine Moore
`
`7/15/2009 11:19:42 AM
`CHEMIST
`
`

`

`NDA 22-341
`
`Victoza®
`
`Liraglutide Injection
`
`Novo Nordisk Inc. '
`
`Joseph Leginus, PhD
`Division of Pre—Marketing Assessment 1
`Office of New Drug Quality Assessment
`
`Division of Metabolism and Endocrinology Products
`HFD-510
`
`CHEMISTRY REVIEW #2
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Table of Contents
`
`Table of Contents
`
`.....................
`
`.................. .. .................................................. 2
`
`Chemistry Review Data Sheet........................................................................... ......3
`
`The Executive Summary ................................................................ ......................... 7
`
`1. Recommendations ...................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 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 ......................................................... 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 .............................................................................................9
`
`A APPENDICES ............................................................................................................................... 35
`
`Page 2 of 38
`
`

`

`
`
`
`CHEMISTRY REVIEW ;
`i
`:1
`
`Chemistry Review Data Sheet
`
`' Chemistry Review Data Sheet
`
`1. NDA 22-341
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: 14-Apr-2009
`
`4. REVIEWER: Joseph Leginus
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Original NDA
`Amendment
`Amendment
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissiong s) Reviewed
`NDA Amendment
`
`Document Date
`
`23-May-2008
`25-Aug—2008
`19-Dec-2008
`
`Document Date
`1 1-Feb-2009
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`Novo Nordisk Inc.
`
` Name:
`
`
`
`Address: 100 College Road West, Princeton, NJ 08540
`
`Representative: Mary Ann McElligott, PhD, Assoc. Vice President Regulatory Affairs
`
`
`
`Telephone: (609) 987-5831
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Victoza®
`b) Non-Proprietary Name (USAN): Liraglutide
`0) Code Name/# (ONDC only): NNC 90-] 170, NN2211
`d) Chem. Type/Submission Priority (ONDC only):
`0 Chem. Type: 1
`0
`Submission Priority: Standard
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`Page 3 of 38
`
`

`

`
`
`
`
`CHEMISTRY REVIEW ‘
`
`
`
`‘
`
`Chemistry Review Data Sheet
`
`10. PHARMACOL. CATEGORY:
`Glycemic control in patients with type 2 diabetes
`
`11. DOSAGE FORM: Solution for injection
`
`12. STRENGTH/POTENCY: 6 mg/mL
`
`13. ROUTE OF ADMINISTRATION: Subcutaneous injection
`
`14. RX/OTC DISPENSED:
`
`_X_RX
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`X SPOTS product - Form Completed (9/11/2008)
`Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`USAN: Liraglutide
`C172H265N43O51 (MW = 3751.20 D3)
`
`7
`
`10
`
`HzN—His-Ala-GIu-GIy-Thr—Phe—Thr-Ser—Asp-Val-Ser—Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala
`
`HO
`‘N% Glu-Phe—lle-Ala-Trp—Leu—Val-Arg-Gly-Arg—Gly—COOH
`
`(V ”32" '
`Glu-spacer TI;
`
`NH
`
`O
`
`HOOC/\NH
`‘
`We
`Palmitic acid
`
`Page 4 of38
`
`

`

` .-
`
`
`» CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFS:
`
`
`ITEM
`DATE
`REVIEW
`REFERENCED
`COMPLETED
`Letter of
`Reviewed by
`Yvonne Yang Authorization
`. 9/ 1 5/2001
`9/26/2007
`
`COMMENTS
`
`9/26/2007
`
`Letter of
`Reviewed by
`Yvonne Yang Authorization
`9/16/2001
`
`lAction codes for DMF Table:
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type I 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)
`
`B. Other Documents:
`
`
`DOCUMENT
`APPLICATION NUMBER
`IND
`61,040
`
`
`
`DESCRIPTION
`NNC 90-1170 GLP-l Analo
`
`Page 5 of38
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`18. STATUS:
`
`ONDC:
`
`CONSULTS/ CMC
`RELATED REVIEWS
`
`EES
`
`Pharm/Tox
`
`
`
`
`
`Biopharm/ClinPhann
`
`Methods Validation
`
`CDRH
`
`
`
`Microbiology
`
`
`
`clinical issues required
`before conclusion can be
`Sajjad H. Syed. See Review In
`made that the device can be
`13-Feb-2009
`Appendix 1.
`
`safely and effectively used
`
`
`with the proposed drug.
`
`Labeling consult requested
`as part OND’s labeling
`review.
`’
`
`
`Categorical exclusion
`
`granted as per 21 CFR
`25.31.
`
`
`This submission is
`
`recommended for approval
`
`on the basis of product
`
`uality microbiology.
`
`Overall Acceptable
`recommendation.
`
`
`RECOMMENDATION
`REVIEWER
`
`23—Mar-2009
`Compliance
`
`Qualification of impurities
`conducted according to
`ICH Q6B for
`Biotech/Biological
`Products
`
`
`
`Not applicable. This is an
`injectable product, and the
`
`commercial formulation
`was used in Phase 3
`studies.
`
`
`
`
`Not applicable. Standard
`analytical test methods
`
`emploEd.
`Clarification of certain
`
`
`
`
`
`12-Dec-2008
`
`Joseph Leginus
`
`
`4-Mar-2009
`Bryan S. Riley, Ph.D.
`
`
`19. ORDER OF REVIEW: N/A
`
`The application submission(s) covered by this review was taken in the date order of receipt.
`_X_ Yes
`No.
`If no, explain reason(s) below:
`
`Page 6 of 38
`
`

`

`
`
`CHEMISTRY REVIEW;
`
`Executive Summary Section ,
`
`The Chemi
`
`stry Review for NDA 22-341
`
`The Executive Summary
`
`1.
`
`Recommendations
`
`Recommendation and Conclusion on Approvability
`A.
`NDA 22-341 is recommended for Approval from the standpoint ofchemistry, manufacturing and
`controls.
`
`II.
`
`Summary of Chemistry Assessments
`
`Description of the Drug Product(s) and Drug Substance(s)
`A.
`DRUG SUBSTANCE: Liraglutide is a fragment ofthe naturally occurring human GLP-l (Glucagon-like
`peptide-1) sequence posuion 7-37 having two modifications: 1) substitution ofthe naturally occurring
`lysine amino acid residue in position 34 by arginine, and 2) addition ofa glutamic acid-spaced palmitic
`
`histidyl—L-alanyl-L-a—glutamylglycyl-L-threonyl—L-pheny1alanyl-L-threonyl-L-seryl-L-u-aspartyl-L-
`valyl-L-seryl-L-seryl-L—tyrosyl-L-leucyl—L-a—glutamylglycyl-Lglutaminyl—L-alanyl-L-alany1-N6-[N-( 1—
`oxohexadecyl)—L-y-g1utamyl]-L-lysy1—L—a-glutamyl-L-phenyla1anyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-
`leucyl—L-valyl-L-arginylglycyl-L—arginyl-, and its structure is presented below:
`
`0
`
`NH
`
`Glu-spacer r
`
`HOOC/\NH
`WWO
`.
`.
`Palmitic acid
`The molecular formula of liraglutide is C172H265N43051 with a molecular weight of 375 1 .20.
`Liraglutide is characterized as a
`
`ff/K'J
`
`Liraglutide precursor is produced b
`The manufacturing process is a — y recombinant DNA technology form yeast Saccharomyces cerevisiae.
`'_. “)a
`
`Page 7 of38
`
`

`

`CHEMISTRY REVIEW
`I Executive Summary Section
`
`\ ‘
`
`\
`
`_
`
`_1
`
`,
`
`‘
`
`\ W
`
`A shelf life of 24 months will be granted for the drug substance when stored at -18°C i2°C/ambient RH
`or lower temperatures. This is based on real-time studies obtained from primary stability data conducted
`on pilot scale production batches (Batch Numbers G1K4SOO9, G1K4SOIO and G1K4S01 1 from
`Campaign 6) of the drug substance.
`
`DRUG PRODUCT: Liraglutide injection is a parenteral drug product for subcutaneous administration. It
`is supplied in multiple-dose pre-filled pen—injectors ‘M
`
`. The drug product is
`filled in a glass cartridge and assembled at the
`manufacturing facility into a disposable multi—dose pen injector. Each pen-injector contains 3 mL of drug
`product at a concentration of 6 mg/mL. The delivered dose of each injection is 0.6 mg, 1.2 mg or 1.8 mg
`depending on the setting of the multi—dose injector. ———7e—-—-———_—_—~'—-
`
`Wm
`
`h
`b(4j
`
`The drug product consists ofan aqueous formulation at pH 8.15 of ’— liraglutide with ._ disodium
`
`phosphate dihydrate
`propylene glycol wf—N and
`
`phenol
`
`The three pilot drug product batches (SQ50423, SQ50447, SQ50549) are regarded to be the primary
`stability batches, found acceptable by FDA at the pre—NDA stage, and were considered for assessing real
`time stability. Review of the data for these batches through 30 months of real time stability at 2 - 8°C
`show that the liraglutide 6.0 mg/mL drug product remains within the shelf life specification limits during
`this time. The in-use stability evaluation was performed for 32 days at 28 - 32°C using drug product
`batches a) newly produced, and b) after 24 months of storage at the recommended storage conditions of 2
`- 8°C. In——use stability was evidenced when tested under all configurations (newly produced filled, newly
`produced half—filled 24 month stored filled) As a result, an expiry of 24 months at 2— 8°C plus 32 days
`at 28— 32°C15 granted for the drug product.
`
`B.
`
`Description of How the Drug Product is Intended to be Used
`
`Liraglutide is intended as an adjunct to diet and exercise to achieve glycemic control in patients with type
`2 diabetes mellitus. Liraglutide is developed for once-daily administration as:
`'
`' 'Monotherapy
`- Combination therapy with one or more oral antidiabetic drugs (metformin, sulphonylureas or a
`thiazolidinedione) when previous therapy does not achieve adequate glycemic control.
`Liraglutide is designed for multidose use and is administered once daily at any time, independent of
`meals. It can be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection
`site and timing can be changed without dose adjustment. For all patients, liraglutide should be initiated
`with a dose of 0.6 mg for at least one week, after which the dose should be increased to 1.2 mg. Based on
`clinical response and after at least one week, the dose can be increased to 1.8 mg to achieve maximum
`efficacy.
`'
`
`Page 8 of 38
`
`

`

`
`
`if
`CHEMISTRY REVIEW i
`
`Executive Summary Section
`
`C.
`
`Basis for Approvability or Not-Approval Recommendation
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`See electronic signature page
`
`B. Endorsement Block
`
`Chemist Name/Date: J. Leginus/Date
`Chemistry Team Leader: S. Tran/Date
`Project Manager: J. Bishai/Date
`
`C. CC Block
`
`Chemistry Assessment
`
`Drug Substance
`
`Page 9 of38
`
`

`

`29 ’
`
`Page(s) Withheld
`
`X a
`
`Trade Secret / Confidential (b4)
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)}
`
`‘
`
`Deliberative Process (b5)
`
`Withheld Truck Number: Chemistry- _1_
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Joseph Leginus
`4/17/2009 12:23:10 PM
`CHEMIST
`
`Ali Al—Hakim
`4/17/2009 03:07:25 PM
`CHEMIST
`
`

`

`CHEMISTRY REVIEW
`
`NDA 22-341
`
`Victoza®
`
`Liraglutide Injection
`
`Novo Nordisk Inc.-
`
`JoSeph Leginus, PhD
`Division of Metabolism and Endocrinology Products
`HFD-510
`
`

`

`
`
`Table of Contents
`
`Table of Contents ...............................
`
`................................................................2
`
`Chemistry Review Data Sheet.............................................................................. ...3
`
`The Executive Summary ............ ...................................................................
`
`......7
`
`1. 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
`
`III. Administrative ........................................................................................................ 9
`
`A. Reviewer’s Signature .................................................. ’. ........................................9
`
`B. Endorsement Block ............................................................................................. 9
`
`C. CCBlocklO
`
`ChemistryAssessment7
`
`1. Review Of Common Technical Document-Quality (Ctd—Q) Module 3.2: Body Of Data.1 l
`
`s DRUG SUBSTANCE [Name, Manufacturer].............................................................:11.
`
`P DRUG PRODUCT [Name, Dosage form] .................................................................61:
`
`A APPENDICES.................................; ............................................................................................£105
`
`R REGIONAL INFORMATION ............................................................................. 106
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ...................................1108‘
`
`A. Labeling & Package Insert ....................................................................................... 108
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ........................................... 110
`
`111. List Of Deficiencies To Be Communicated ....................................................................1'17
`
`

`

` ' CHEMISTRY REVIEW .
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 22-341
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 19-Dec-2008
`
`4. REVIEWER: Joseph Leginus
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Original NDA
`Amendment
`
`_
`
`Document Date
`
`23-May-2008
`25-Aug-2008
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission( 5) Reviewed
`Original NDA
`
`Document Date
`23-May-2008
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`
`
`
`(609) 987-5831
`
`
`
`
`
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Victoza®
`b) Non-Proprietary Name (USAN): Liraglutide
`0) Code Name/# (ONDC only): NNC 90-1170, NN2211'
`d) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 1
`
`0 Submission Priority: Standard
`
`Page 3 of12l
`
`

`

` CHEMISTRY REVIEW,
`
`Chemistry Review Data Sheet
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY:
`
`Glycemic control in patients with type 2 diabetes
`
`11. DOSAGE FORM: Solution for injection
`
`12. STRENGTH/POTENCY: 6 mg/mL
`
`13. ROUTE OF ADMINISTRATION: Subcutaneous injection
`
`14. Rx/OTC DISPENSED:
`
`X RX
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM):
`
`X SPOTS product - Form Completed (9/11/2008)
`Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`USAN: Liraglutide
`C172H265N43051 (MW 2 3751.20 Da)
`
`'
`
`37
`34
`H o
`10
`7
`HZN—His—AIa-Glu—Gly-Thr-Phe—Thr-Ser—Asp—Val-Ser-Ser—Tyr— Leu—GIu-Gly-G ln-Ala-Ala - N \/U— Glu-Phe-l le—A]a—Trp—Leu—Val—Arg—GIy-Arg—GIy-—COOH
`
`(r Lys26
`Glu-spacer I
`
`ONH
`
`HOOC/\NH
`W0
`Palm'itic acid
`
`Page 4 of 121
`
`

`

`
`
`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`
`ITEM
`
`REFERENCED
`
`STATUS2
`
`DATE
`REVIEW
`COMPLETED .
`
`COMMENTS
`
`
`
`Reviewed by
`
`11(4)
`
`Reviewed by
`
`‘ Act1on codes for DMF Table:
`l — 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)
`
`B. Other Documents:
`
`DOCUMENT
`APPLICATION NUMBER
`
`61.040
`
`DESCRIPTION
`
`NNC 90-1170 GLP-l Analog
`
`18. STATUS:
`
`
`
`DATE
`
`REVIEWER
`
`ONDC:
`CONSULTS/ CMC
`RELATED REVIEWS
`
`Pharm/Tox
`
`RECOMMENDATION
`Pending. EER was sent to
`Office of Compliance on
`12—Jun-2008.
`
`To be determined by CMC
`reviewer. A consult review
`
`may be needed for the
`safety evaluation of
`
` .
`leachables and im nurities.
`
`.
`Biopharm/ClmPharm
`
`May not be applicable.
`This is an in'ectable
`
`Page 5 of121
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Methods Validation
`
`Chemistry Review Data Sheet
`
`
`product, and the
`commercial formulation
`
`was used in Phase 3
`
`
`studies.
`
`Validation may be
`
`
`
`requested of FDA labs after
`
`test methods are finalized.
`
`
`
`
`
`
`
`Labeling consult request
`ODS/DMETS
`will be sent as part of
`
`
`DMEP’s request.
`
`
`To be done by CMC
`
` 12-Dec-2008
`
`Joseph Leginus
`reviewer.
`
`Review of l) microbiology
`controls proposed for the
`
`drug substance and drug
`
` Microbiology
`product, and 2) sterilization
`
`and
`7"” (“processing
`
`validation for the drug
`
`
`roduct.
`
`
`
`
`
`
`
`multi-dose oen 1n ector.
`
`l9. ORDER OF REVIEW: N/A
`
`The application submission(s) covered by this review was taken in the date order of receipt.
`_X_ Yes
`No.
`If no, explain reason(s) below:
`
`Page 6 olel
`
`(b) (4)
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`The Chemistry Review for NDA 22-341
`
`The Executive Summary
`
`I.
`
`Recommendations
`
`Recommendation and Conclusion on Approvability
`A.
`NDA 22-341 is recommended for Approvable from the standpoint of chemistry, manufacturing and controls pending
`1) a satisfactory response to the deficiencies delineated in the Draft List of Deficiencies and Information Request (in
`the CMC reviews forNDA 22-341).
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable — Not applicable
`
`II.
`
`Summary of Chemistry Assessments
`
`A.
`
`Description of the Drug Product(s) and Drug Substance(s)
`
`DRUG SUBSTANCE: Liraglutide is a fragment of the naturally occurring human GLP-l (Glucagon-like peptide-1)
`sequence position 7-37 having two modifications: ]) substitution of the naturally occurring lysine amino acid
`residue in position 34 by arginine, and 2) addition of a glutamic acid-spaced palmitic acid to the s—amino group of
`lysine in position 26. Liraglutide precursor is produced using recombinant DNA technology in yeast
`(Saccharomyces cerevisiae). The chemical name of liraglutide is glycine, L-histidyl-L-alanyl—L-a-glutamylglycyl-L-
`threonyl—L—phenylalanyl—L—threonyl—L-seryl—L-a-aspartyl—L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-a-
`glutamylglycyl-Lglutaminyl-L-alanyl-L-alanyl-N6-[N-(l-oxohexadecyl)—L-y-glutamyl]-L—lysyl-L-a-g1utamyl-L-
`phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L—leucyl-L—valyl-L-arginylglycyl-L-arginyl-, and its structure is
`presented below:
`
`37
`34
`H O
`,
`10
`7
`HZN— His-Ala-Glu-G1y-Thr-Phe—Thr-Ser—Asp-Val-Ser—Ser-Tyr—Leu—Glu—Gly-Gln-Ala-Ala- N \)-L— Glu-Phe-lle-Ala-Trp-Leu- Val -Arg-Gly-Arg—Gly--COOH
`
`(l/ LySZ6
`Glu-spacer j;
`
`NH
`
`O
`
`.
`HOOC/\NH
`W0
`Palmitic acid
`
`The molecular formula of liraglutide is C172H265N43051 with a molecular weight of 3751.20.
`
`Liraglutide is characterized as a /
`
`Page 7 of121
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`The structure of liraglutide was elucidated by a variety of analytical and spectrophotometric techniques, including
`amino acid analysis (AAA), amino acid sequencing, mass spectrometry (MALDI-TOF MS), circular dichroism
`(CD) and peptide mapping.
`
`Liraglutide precursor is produced by recombinant DNA technology form yeast Saccharomvces cerevisiae. The
`manufacturing process is a /W i v')
`and purification (steps—- ) The purification process consists of purification of the liraglutide precursor (steps I
`’zW .
`.__).
`
`The proposed release specifications include appearance, identification (peptide mapping and HPLC), content
`
`(HPLC), specific bioactivity (cAMP assay),
`.——————-—-
`related impurities and
`related impurities
`
`(HPLC),
`, bacterial endotoxin, total viable count and host cell protein (ELISA). The proposed
`regulatory methods have been validated. Reference standards for the API have been developed and characterized.
`
`Product related impurities structurally related to liraglutide generated during the fermentation, recovery, purification
`or storage of the drug substance have classified based on their RP-HPLC elution position relative to the drug
`substance. These have been characterized as “ ‘—~——-
`liraglutide related impurities”, “liraglutide related
`impurities A”, “liraglutide related impurities B”, “liraglutide related impurities C”, and “.P‘.
`liraglutide related impurities.” The sum of product related impurities during pilot and manufacturing scale ranged
`
`from
`’/o. Process derived impurities originating from the liraglutide manufacturing process were not
`detected in the drug substance.
`
`51(4)
`
`A shelf life of #will be granted for the drug substance when stored at f’C i2°C/ambient RH or lower
`temperatures. This is based on real-time studies obtained from primary stability data conducted on pilot scale
`production batches (Campaign 6) of the drug substance.
`
`DRUG PRODUCT: Liraglutide injection is a parenteral drug product for subcutaneous administration. It is
`supplied in multiple--dose pre--filled pen-injectorsN
`
`
`.The drug product18
`filledin a glass cartridge and assembled into a disposable multi-dose pen
`injector. Each pen-injector contains 3 mL of drug p1oduct at a concentration of 6 mg/mL. The delivered dose of each
`injection is 0.6 mg, 1.2 mg or 1.8 mg depending on the setting ofthe multi-dose injector. ( l————-—-_;W
`&—————-\————.—————————-—-—-———-f
`
`The drug product consists of an aqueous formulation at pH 8.15 of ‘— Vo liraglutide with —'/o disodium phosphate
`
`
`dihydrate ———-——————- -% propylene glycol
`and ——1% phenol "-
`
`A close correlation has been documented between biological activity of liraglutide and content by HPLC under both
`normal and stressed conditions for the drug product. As a result, it has been determined that the HPLC assay is able
`to offer a reliable indication of the biological activity of liraglutide in the drug product. Therefore, bioactivity is not
`included in the proposed drug product specification.
`
`The proposed release specifications include appearance, identification (HPLC), content (HPLC), pH, individual
`———-—related impurities and total / related impurities (HPLC), bacterial endotoxin, sterility, phenol content,
`
`53(4)
`
`Page 8 of121
`
`

`

` CHEMISTRY REVIEW
`
`Executive Summary Section
`
`particulate matter, freezing point depression (osmolality) and dose accuracy. The proposed regulatory methods have
`been validated.
`
`No new-impurities were found in the drug product compared to the drug substance. The liraglutide drug product is
`photo labile and the primary container does not provide adequate protection from exposure to light. However, the
`secondary packaging (pen-injector) adequately protects the drug product from degradation due to light.
`
`The three pilot drug product batches (SQ50423, SQ50447, SQ50549) are regarded to be the primary stability
`batches, found acceptable by FDA at the pre-NDA stage, and were considered for assessing real time stability.
`Review of the data for these batches through [nonths of real time stability at 2 — 8°C show that the liraglutide 6.0
`mg/mL drug product remains within the shelf life specification limits during this time. The in-use stability
`evaluation was performed for 32 days at 28 - 32°C using drug product batches a) newly produced, and b) afier/
`months of storage at the recommended storage conditions of 2 — 8°C. In-use stability was evidenced when tested
`under all configurations (newly produced filled, newly produced half-filled, / month stored filled). As a result, an
`expiry of/ months at 2 — 8°C plus 32 days at 28 — 32°C is granted for the drug product. (The applicant’s proposal
`of a / month shelf life period is not warranted).
`
`51(4)
`
`Novo Nordisk requested a categorical exclusion from submitting an environmental assessment for the drug product
`liraglutide 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
`
`Liraglutide is intended as an adjunct to diet and exercise to achieve glycemic control in patients with type 2 diabetes
`mellitus. Liraglutide is developed for once-daily administration as:
`- Monotherapy
`- Combination therapy with one or more oral antidiabetic drugs (metformin, sulphonylureas or a
`thiazolidinedione) when previous therapy does not achieve adequate glycemic control.
`Liraglutide is designed for multidose use and is administered once daily at any time, independent of meals. It can be
`injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site and timing can be
`changed without dose adjustment. For all patients, liraglutide should be initiated with a dose of 0.6 mg for at least
`one week, after which the dose