CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`206321Orig1s000
`
`CHEMISTRY REVIEW(S)
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`

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`MEMORANDUM
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`
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`Date: 21—Oct—20 14
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`From: Joseph Leginus, Review Chemist, Branch VII/DNDQA III/ONDQA
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`To: NDA 206321, SaxendaTM (Liraglutide [rDNA origin] Injection)
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`Subject: CMC Approval Recommendation
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`Background:
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`In Chemistry Review #1 (14—May—2014), the recommendation from the standpoint of
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`chemistry, manufacturing and controls was Approval for NDA 206321. However, at
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`that time, a recommendation from the Office of Compliance was pending.
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`o On 16-Jan-2014, a recommendation for Approval was provided by the Microbiology
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`Reviewer, B. Riley.
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`Update:
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`0 On 10—Oct-2014, a recommendation of Acceptable was provided by the Office of
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`Compliance for NDA 206321.
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`Conclusion:
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`- NDA 206321 is recommended for Approval from the standpoint of chemistry,
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`manufacturing and controls. A recommendation for Approval has been provided from
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`Microbiology and an overall Office of Compliance recommendation of Acceptable
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`has been provided.
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`Joseph Leginus, PhD
`Review Chemist
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`-
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`-
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`Digitally signed by
`Jose p h ‘leg I n U S@fd a ' h h josephJeginus@fda.hhs.gov
`
`
`
`DN: cn=joseph.leginus@fda.hhs.gov
`5-9 0V
`Date: 2014.10.21 07:25:44 -O4'OO'
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`

`

`CHEMISTRY REVIEW
`
`NDA 206321
`Saxenda™
`(Liraglutide [rDNA origin] Injection)
`
`Novo Nordisk Inc.
`
`Joseph Leginus, PhD
`Division of Pre-Marketing Assessment III, Branch VII, ONDQA
`
`For the Division of
`Metabolism and Endocrinology Products
`
`CHEMISTRY REVIEW #1
`
`Reference ID: 3506373
`
`

`

`CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`I. Recommendations......................................................................................................................7
`A. Recommendation and Conclusion on Approvability.......................................................................7
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable...................................................................................................7
`
`II. Summary of Chemistry Assessments.........................................................................................7
`A. Description of the Drug Product(s) and Drug Substance(s) .............................................................7
`B. Description of How the Drug Product is Intended to be Used..........................................................8
`C. Basis for Approvability or Not-Approval Recommendation............................................................9
`
`III. Administrative...........................................................................................................................9
`A. Reviewer’s Signature:
`in DAARTS .............................................................................................9
`B. Endorsement Block:
`in DAARTS..................................................................................................9
`C. CC Block:
` in DAARTS ...............................................................................................................9
`Chemistry Assessment...........................................................................................10
`
`I. Review of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body of Data ..........10
`S DRUG SUBSTANCE....................................................................................................................10
`P DRUG PRODUCT ........................................................................................................................10
`A APPENDICES ...............................................................................................................................22
`R REGIONAL INFORMATION ......................................................................................................22
`
`II. Review of Common Technical Document-Quality (Ctd-Q) Module 1 ...................................23
`A. Labeling & Package Insert.............................................................................................................23
`B. Environmental Assessment or Claim of Categorical Exclusion ....................................................28
`List of Deficiencies To Be Communicated ..........................................................................................29
`
`Reference ID: 3506373
`
`

`

`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 206321
`2. REVIEW #: 1
`3. REVIEW DATE: 14-May-2014
`4. REVIEWER: Joseph Leginus, PhD
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`N/A
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission(s) Reviewed
`Original NDA
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`Document Date
`20-Dec-2013
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`Novo Nordisk Inc.
`
`PO Box 846, Plainsboro NJ, 08536
`
`Robert B. Clark, VP, Regulatory Affairs
`
`609-786-4690
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Saxenda™
`b) Non-Proprietary Name (USAN): Liraglutide
`c) Code Name/# (ONDC only): Liraglutide 3 mg
`d) Chem. Type/Submission Priority (ONDC only):
` Chem. Type: Type 1
` Submission Priority: Standard
`
`9. LEGAL BASIS FOR SUBMISSION: This NDA is submitted as a 505(b)(1)
`application.
`
`Reference ID: 3506373
`
`Page 3 of 29
`
`

`

`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`10. PHARMACOL. CATEGORY: Chronic weight management
`
`11. DOSAGE FORM: Injectable solution
`
`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):
` SPOTS product – Form Completed
`
` X Not a SPOTS product
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name (USAN): Liraglutide
`Structural Formula:
`
`Molecular Formula: C172H265N43O51
`Molecular Weight: 3751.2 Da
`
`Reference ID: 3506373
`
`Page 4 of 29
`
`

`

`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DMF
`#
`
`TYPE
`
`HOLDER
`
`ITEM
`REFERENCED CODE1 STATUS2
`
`DATE
`REVIEW
`COMPLETED
`
`V
`
`V
`
`1
`
`1
`
`Adequate
`
`8/12/2011
`
`Adequate
`
`5/30/2012
`
`COMMENTS
`
`Reviewed by
`S. Langille
`
`Reviewed by
`V. Pawar
`
`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)
`
`B. Other Documents:
`
`DOCUMENT
`NDA
`IND
`
`APPLICATION NUMBER
`22341
`73206
`
`DESCRIPTION
`Victoza® (liraglutide [rDNA] injection)
`Liraglutide Injection
`
`Reference ID: 3506373
`
`Page 5 of 29
`
`(b) (4)
`
`(b) (4)
`
`

`

`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`18. STATUS:
`ONDC:
`CONSULTS/ CMC
`RELATED REVIEWS
`EES
`
`RECOMMENDATION
`Pending.
`N/A.
`
`
`
`DATE
`
`REVIEWER
`N/A
`
`Pharm/Tox
`
`
`
`Biopharmaceutics
`
`14-May-2014
`
`J. Leginus
`
`1/16/2014
`
`B. Riley
`
`.
`“No Biopharm review/er is
`needed for this NDA.”
`(12/24/2013 email from T.
`Ghosh, Biopharm Team
`Leader).
`Not required. No novel
`methods.
`Categorical Exclusion
`Granted under 21 CFR
`§25.31(b).
`Approval
`Microbiology
`19. ORDER OF REVIEW: N/A
`
`Methods Validation
`
`EA
`
`Reference ID: 3506373
`
`Page 6 of 29
`
`(b) (4)
`
`

`

`CHEMISTRY REVIEW
`Executive Summary Section
`The Chemistry Review for NDA 206537
`The Executive Summary
`I.
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The recommendation from a CMC perspective is Approval.
`
`At this time, a recommendation from the Office of Compliance is pending.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`Not applicable.
`Summary of Chemistry Assessments
`
`II.
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`DRUG SUBSTANCE
`
`Liraglutide is a fragment of the naturally occurring human GLP-1 (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 ε-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-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-
`L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-α-glutamylglycyl-Lglutaminyl-L-alanyl-L-
`alanyl-N6-[N-(1-oxohexadecyl)-L-γ-glutamyl]-L-lysyl-L-α-glutamyl-L-phenylalanyl-L-
`isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-arginylglycyl-L-arginyl-, and its
`structure is presented below:
`
`Reference ID: 3506373
`
`Page 7 of 29
`
`

`

`CHEMISTRY REVIEW
`Executive Summary Section
`
`The molecular formula of liraglutide is C172H265N43O51 with a molecular weight of
`3751.20.
`
`Liraglutide is characterized as a white to almost white powder. It is freely soluble in
`aqueous base solutions (> 270 mg/mL), but its water solubility decreases below pH 7 and
`reaches its lowest level at pH 4-5 (approximately 0.05 mg/mL). Solubility increases
`marginally at pH 2.5 where it is very slightly soluble (≤ 0.8 mg/mL). Liraglutide is
`soluble in methanol (68 mg/mL) and very slightly soluble in ethanol (1.1 mg/mL). The
`isoelectric point of liraglutide is approximately 4.9. The pH of a 1 mg/mL aqueous
`solution of drug substance is approximately 9.3.
`
`DRUG PRODUCT
`
` liraglutide with
`Liraglutide 3 mg consists of an aqueous formulation at pH 8.15 of
` disodium phosphate dihydrate
` propylene glycol
`
` and
` phenol
`
`Liraglutide 3 mg is a parenteral drug product for subcutaneous administration. The drug
`product is
` filled in a 3 mL glass cartridge and assembled 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, 1.8
`mg, 2.4 mg or 3.0 mg depending on the setting of the multi-dose pen-injector.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The proposed indication for Liraglutide 3 mg is as an adjunct to a reduced-calorie diet
`and increased physical activity for chronic weight management in adult patients.
`Liraglutide 3 mg is administered once daily at any time, independent of meals, and can be
`injected subcutaneously in the abdomen, in the thigh or in the upper arm. The starting
`dose is 0.6 mg and is intended to be increased with 0.6 mg weekly increments until the
`maintenance dose of 3 mg is achieved. The 0.6, 1.2, 1.8 and 2.4 mg doses are intended to
`reduce gastrointestinal symptoms during initial dose escalation.
`
`Reference ID: 3506373
`
`Page 8 of 29
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`CHEMISTRY REVIEW
`Executive Summary Section
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The recommendation from a CMC perspective is Approval.
`
`This is a 505(b)(1) application for a new indication (chronic weight management) for the
`same approved drug product Victoza® (liraglutide [rDNA] injection) of NDA 22341
`(glycemic control in patients with type 2 diabetes). The applicant is the same for both
`NDAs.
`
`The drug products of the two NDAs have the same a) drug substance,
` Both NDAs use the identical 3 mL
`glass cartridge as the primary container closure system. The 3 mL glass cartridge for
`liraglutide 3 mg will be provided in a different pen-injector referred to as the PDS290
`pen-injector for liraglutide (PDS290). The PDS20 is capable of delivering 5 different
`doses of Liraglutide: 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg and 3.0 mg.
`
`
`
`Data provided from the stressed stability and photostability studies for Liraglutide 3 mg
`do not show evidence of any changes to the stability compared to the approved Victoza®
`(NDA 22341). The applicant’s proposal that the long-term and in-use shelf lives of the
`approved product should apply to the new product as bridged by 3-month data under
`stressed conditions of 37°C for the product in cartridges alone and product in cartridges
`assembled in the new pen injector is acceptable. Therefore, the shelf life and the in-use
`conditions for Liraglutide 3 mg using the PDS290 pen-injector
`
` i.e., an expiry of months at 2°C – 8°C plus
`days at 28°C – 32°C is granted for the drug product.
`
`
`
`Biopharmaceutics concluded that “No Biopharm review/er is needed for this NDA.”
`(12/24/2013 email from T. Ghosh, Biopharm Team Leader).
`
`Microbiology has provided an Acceptable recommendation.
`
`A recommendation from the Office of Compliance for manufacturing facilities associated
`with this application is pending.
`
`The risk associated with Saxenda® is low. With the exception of the pen-injector,
`Saxenda is the same drug product as the Applicant’s approved Victoza® (liraglutide
`[rDNA] injection; NDA 22341) intended for the treatment of diabetes. The pen injector is
`under review by CDRH.
`
`III. Administrative
`
`A. Reviewer’s Signature:
`B. Endorsement Block:
`C. CC Block:
`
`in DAARTS
`in DAARTS
`in DAARTS
`
`Reference ID: 3506373
`
`Page 9 of 29
`
`20 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`(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/
`----------------------------------------------------
`
`JOSEPH LEGINUS
`05/14/2014
`
`DANAE D CHRISTODOULOU
`05/14/2014
`
`Reference ID: 3506373
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`IQA and Filing Review Cover Sheet
`
`1. NEW DRUG APPLICATION NUMBER: 206321
`2. DATES AND GOALS:
`Submission Received Date : 20-DEC-2013
`Letter Date: 20-DEC-2013
`PDUFA Goal Date: 20-OCT-2014 (NDA is NOT in “The Program”)
`3. PRODUCT PROPERTIES:
`Proposed: Saxenda
`Trade or Proprietary Name:
`Liraglutide
`Established Name (USAN):
`Injectable solution
`Dosage Form:
`Subcutaneous injection
`Route of Administration
`6 mg/mL
`Strength/Potency
`Rx
`Rx/OTC Dispensed:
`4.
`INDICATION: Chronic weight management
`5. DRUG SUBSTANCE STRUCTURAL FORMULA:
`
`6. NAME OF APPLICANT (as indicated on Form 356h): Novo Nordisk Inc.
`7. SUBMISSION PROPERTIES:
`Review Priority (select one)
`Standard
`Submission Classification
`10
`(Chemical Classification Code)
`
`Page 1of 7
`
`Reference ID: 3440795
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`Application Type
`Breakthrough Therapy
`Responsible Organization
`(Clinical Division)
`8. CONSULTS:
`CONSULT
`Biometrics
`Clinical Pharmacology
`Establishment Evaluation
`Request (EER)
`Pharmacology/Toxicology
`Methods Validation
`Environmental Assessment
`CDRH
`
`505(b)(1)
`No
`Division of Metabolism and Endocrinology Products
`CMC Lead: Suong (Su) Tran
`
`YES NO
`x
`x
`
`x
`
`x
`
`x
`
`COMMENTS:
`
`To be sent by ONDQA-PM
`
`To be determined by Primary Reviewer
`Categorical exclusion request to be reviewed by Primary
`Reviewer
`Review of pen injectors
`
`Does the submission contain any of the following elements? No
`Nanotechnology
`QbD Elements
`PET
`
`Other, please explain
`
`Is a team review
`recommended?
`
`No - Reference is made to the approved NDA 22341 for all CMC
`information on the drug substance and drug product, with the exception
`of information on the new pen injector of the new NDA and stability data
`of the product assembled in the new pen. One CMC reviewer will review
`the new stability data and labeling.
`
`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:n/a
`
`Microbiology:
`Is the Product Quality Section of the application fileable from a Microbiology perspective?
`
`Page 2of 7
`
`Reference ID: 3440795
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`See Microbiology Filing Review in DARRTS for details and for any potential Microbiology
`review issues.
`
`Previous quality-related meeting between ONDQA and the sponsor: None.
`
`Summary of Critical Issues and Complexities
`This new NDA is for a new indication (weight management) for the same approved product
`Victoza of NDA 22341 (diabetes). Both NDAs have the same applicant.
`The applicant states that the drug products of the two NDAs
`packaged in the same primary container closure system (glass cartridges). The pre-filled
`cartridges will be assembled in two different pen injectors (each pen injector is specific to the one
`NDA). A technical comparison of the pen injectors is included in the NDA. A CDRH consult
`request will be sent by the Clinical Division and will cover CDRH Compliance, human factors
`and technical reviews. CDRH and the Office of Combination Products had several
`communications with the sponsor during the IND development.
`
` are
`
`Reference is made to the approved NDA 22341 for all CMC information on the drug substance
`liraglutide.
`The new NDA includes drug product information that is not the same between the two NDA:
`manufacturing process and stability data.
` The reviewer will note the manufacturing process information that is the same in the two
`NDAs and evaluate the new information.
` The drug product specifications are the same between the two NDAs with the exception
`of the device-specific attribute of Dose Accuracy, which will be part of the CDRH
`technical review (as was done in other NDA reviews).
`Stability data are provided in the NDA in support of the new pen injector, including a
`photostability study report. The three primary stability batches were manufactured at the
`commercial site, commercial scale, and packaged with the commercial cartridges. The
`applicant’s proposal that the long-term and in-use shelf lives of the approved product
`should apply to the new product as bridged by 3-month data under stress conditions of
`37°C for the product in cartridges alone and product in cartridges assembled in the new
`pen injector. The reviewer will compare the new data to all available stability data in
`NDA 22341 in evaluating the applicant’s proposal.
`
`
`
`FILING REVIEW CHECKLIST
`
`The following parameters are necessary in order to initiate a full review, i.e., complete enough to
`review but may have deficiencies. On initial overview of the NDA application for filing:
`
`Parameter
`Is the CMC section organized
`adequately?
`
`1.
`
`Comment
`
`A. GENERAL
`Yes No
`x
`
`Page 3of 7
`
`Reference ID: 3440795
`
`(b) (4)
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`2.
`
`Is the CMC section indexed and
`paginated (including all PDF files)
`adequately?
`3. Are all the pages in the CMC
`section legible?
`Has all information requested
`during the IND phase, and at the
`pre-NDA meetings been
`included?
`
`4.
`
`x
`
`x
`
`x
`
`*
`
`5.
`
`6.
`
`7.
`
`x
`
`B. FACILITIES*
`If any information regarding the facilities is omitted, this should be addressed ASAP with the
`applicant and can be a potential filing issue or a potential review issue.
`Parameter
`Yes No
`Comment
`Is a single, comprehensive list of
`all involved facilities available in
`one location in the application?
`For a naturally-derived API only,
`are the facilities responsible for
`critical intermediate or crude API
`manufacturing, or performing
`upstream steps, specified in the
`application? If not, has a
`justification been provided for this
`omission? This question is not
`applicable for synthesized API.
`
`x
`
`Parameter
`Are drug substance manufacturing
`sites identified on FDA Form 356h or
`associated continuation sheet? For
`each site, does the application list:
` Name of facility,
` Full address of facility including
`street, city, state, country
` FEI number for facility (if
`previously registered with FDA)
` Full name and title, telephone, fax
`number and email for on-site
`contact person.
` Is the manufacturing responsibility
`and function identified for each
`facility?, and
` DMF number (if applicable)
`
`Yes
`
`No
`
`Comment
`
`x
`
`Page 4of 7
`
`Reference ID: 3440795
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`Are drug product manufacturing sites
`are identified on FDA Form 356h or
`associated continuation sheet. For
`each site, does the application list:
` Name of facility,
` Full address of facility including
`street, city, state, country
` FEI number for facility (if
`previously registered with FDA)
` Full name and title, telephone, fax
`number and email for on-site
`contact person.
` Is the manufacturing responsibility
`and function identified for each
`facility?, and
` DMF number (if applicable)
`
`x
`
`Parameter
`Are additional manufacturing,
`packaging and control/testing
`laboratory sites are identified on
`FDA Form 356h or associated
`continuation sheet. For each site,
`does the application list:
` Name of facility,
` Full address of facility
`including street, city, state,
`country
` FEI number for facility (if
`previously registered with
`FDA)
` Full name and title, telephone,
`fax number and email for on-
`site contact person.
` Is the manufacturing
`responsibility and function
`identified for each facility?,
`and
` DMF number (if applicable)
`Is a statement provided that all
`facilities are ready for GMP
`inspection at the time of
`submission?
`
`Yes No
`
`Comment
`
`x
`
`x
`
`C. ENVIRONMENTAL ASSESMENT
`Yes No
`
`Comment
`
`Parameter
`Has an environmental assessment
`or claim of categorical exclusion
`been provided?
`
`x
`
`Page 5of 7
`
`8.
`
`9.
`
`10.
`
`11.
`
`Reference ID: 3440795
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`D.
`
`12.
`
`13.
`
`14.
`
`16.
`
`17.
`
`18.
`
`DRUG SUBSTANCE/ACTIVE PHARMACEUTICAL INGREDIENT (DS/API)
`Parameter
`Yes
`No
`Comment
`Does the section contain a
`Reference is made to the approved NDA
`description of the DS
`22341.
`manufacturing process?
`Does the section contain
`identification and controls of
`critical steps and intermediates of
`the DS
`Does the section contain
`information regarding the
`characterization of the DS?
`15. Does the section contain controls
`for the DS?
`Has stability data and analysis
`been provided for the drug
`substance?
`Does the application contain
`Quality by Design (QbD)
`information regarding the DS?
`Does the application contain
`Process Analytical Technology
`(PAT) information regarding the
`DS?
`
`E.
`
`19.
`
`20.
`
`21.
`
`22.
`
`DRUG PRODUCT (DP)
`Parameter
`Is there a description of
`manufacturing process and
`methods for DP production
`through finishing, including
`formulation, filling, labeling and
`packaging?
`Does the section contain
`identification and controls of
`critical steps and intermediates of
`the DP, including analytical
`procedures and method validation
`reports for assay and related
`substances if applicable?
`Is there a batch production record
`and a proposed master batch
`record?
`Has an investigational
`formulations section been
`provided? Is there adequate
`linkage between the
`investigational product and the
`proposed marketed product?
`
`Yes No Comment
`
`x
`
`x
`
`x
`
`x
`
`Page 6of 7
`
`Reference ID: 3440795
`
`

`

`ONDQA Initial Quality Assessment (IQA) and Filing Review
`For new NDAs
`
`24.
`
`26.
`
`27.
`
`23. Has any biowaiver been
`requested?
`Does the section contain
`description of to-be-marketed
`container/closure system and
`presentations?
`25. Does the section contain controls
`of the final drug product?
`Has stability data and analysis
`been provided to support the
`requested expiration date?
`Does the application contain
`Quality by Design (QbD)
`information regarding the DP?
`Does the application contain
`Process Analytical Technology
`(PAT) information regarding the
`DP?
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`METHODS VALIDATION (MV)
`Parameter
`Yes No Comment
`Is there a methods validation
`x
`package?
`
`MICROBIOLOGY
`Parameter
`If appropriate, is a separate
`microbiological section included
`assuring sterility of the drug
`product
`
`Yes No
`
`x
`
`Comment
`
`28.
`
`F.
`
`29.
`
`G.
`
`30.
`
`H.
`
`31.
`
`MASTER FILES (DMF/MAF)
`Parameter
`Is information for critical DMF
`references (i.e., for drug
`substance and important
`packaging components for non-
`solid-oral drug products)
`complete?
`
`I.
`
`LABELING
`Parameter
`32. Has the draft package insert been
`provided?
`33. Have the immediate container
`and carton labels been provided?
`
`Yes No Comment
`Reference is made to the approved NDA
`22341.
`
`x
`
`Yes No
`x
`
`Comment
`
`x
`
`Page 7of 7
`
`See appended electronic signature page}
`
`Reference ID: 3440795
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SUONG T TRAN
`01/23/2014
`
`DANAE D CHRISTODOULOU
`01/23/2014
`
`Reference ID: 3440795
`
`

`

`Application
`
`NDA 206321I000
`
`NDA 206321/000
`NDA 2063211000
`
`NDA 206321/000
`
`
`NDA 2063211000
`
`NDA 206321I000
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Level1 Levelz Levels Subtype
`
`
`
`N/A
`
`
`
`
`
`
`
`
`
`N/A
`NIA
`N/A
`
`N/A
`
`N/A
`
`
`
`
`
`
`
`Status
`Poplar Sponsor
`
`
`
`N
`NOVO NORDISK INC PM
`
`
`
`NOVO NORDISK INC PM
`NOVO NORDISK INC PN
`
`
`
`NOVO NORDISK INC PN
`
`
`
`
`
`
`NOVO NORDISK INC PN
`
`
`
`NOVO NORDISK INC F‘N
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`N
`N
`N
`
`N
`
`N
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`‘StltusDnte
`
`12/20/2013
`
`
`
`FEI
`
`3002807751
`
`12/20/2013
`12/20/2013
`1Z20/2013
`
`12/20/2013
`
`12/20/2013
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1000158576
`3000151819
`3000151819
`
`
`
`
`
`3003131673
`
`3003131673
`
`
`
`
`
`
`
`Establishment
`CFN
`
`
`9610699 NOVO NORDISK A S
`NOVO NORDISK PHARMACEUTICAL INDUSTRIES
`
`
`
`
`
`INC
`1058438
`
`
`
`9616213 NOVO NORDISK A S
`
`
`9616213 NOVO NORDISK A S
`
`
`
`
`
`
`
`
`9613244 NOVO NORDISK A S
`
`
`
`
`9613244 NOVO NORDISK A S
`
`
`
`
`
`
`
`
`
`
`
`
`
`.
`
`
`
`Address
`
`HALLAS ALLE KALUNDBORG / DNK HALLAS ALLI
`
`
`
`
`
`3612 POWHATAN RD CLAYTON NC/275279217 U1
`NOVO ALLE BAGSVAERD / DNK NOVO ALLE
`
`
`
`
`
`
`NOVO ALLE BAGSVAERD I DNK NOVO ALLE
`
`
`
`
`
`
`
`
`
`
`
`HILLEROD IDK3400 DNK BERNNUM PARK, DK'34
`
`
`
`
`
`HILLEROD IDK3400 DNK BERNNUM PARK, DK-34
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Overall Recommendation - Acceptable
`
`
`
`Overall Re-eval Date - October 20, 2016
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`CTL
`
`b 4
`( )( )
`CTL
`
`(b) (4)
`DKA
`
`DNK
`
`
`
`USA
`DNK
`
`
`
`
`
`
`
`DNK
`DNK
`
`
`DNK
`
`
`
`MANUFACTURER
`FINISHED DOSAGE
`
`
`
`DRUG SUBSTANcE.FINISHED DOSAGE MANUFACTURERpTHER TESTER
`
`
`
`
`DRUG SUBSTANCEFINISHED DOSAGE MANUFACTURER.OTHER TESTER
`
`
`
`
`
`
`FINISHED DOSAGE
`LABELERMANUFACTURER,PACKAGER
`
`
`
`(WW FINISHEDDOSAGE
`
`
`
`
`LABELER,MANUFACTURER,PAOKAGER
`
`
`
`
`
`
`
`
`Coumry
`
`Profile Stags
`
`
`
`
`
`
`1
`
`Last Mlle'slone
`
`
`
`
`Compltance Status
`
`
`
`
`Mllestone Dale
`
`
`
`
`OAI Alert Status
`
`
`
`
`
`EER Re—eval Date
`
`
`
`
`
`DRUG SUBSTANCE
`
`
`
`
`Process
`
`
`
`OTHER TESTER
`
`
`
`
`oc RECOMMENDATION Ac
`
`
`
`
`
`
`oc RECOMMENDATION Ac
`
`
`OC RECOMMENDATION Ac
`
`
`
`oc RECOMMENDATION Ac
`
`
`oc RECOMMENDATION Ac
`
`
`OOREcOMMENDATION Ac
`
`
`
`
`
`
`
`
`2/17/2014
`,
`9/4/2014
`
`2/25/2014
`
`
`
`
`
`2/21/2014
`
`7/30/2014
`
`
`
`7/30/2014
`
`
`
`“NONE“
`
`“NONE”
`“NONE"
`
`“NONE“
`"NONE“
`
`“NONE”
`
`5/10/2016
`
`8/16/2918
`9/3/2016
`
`
`
`
`
`
`9/3/2015
`
`10/10/2016 .
`
`
`10/10/2016
`
`
`
`
`/
`
`:\
`
`‘
`
`1
`
`I
`
`}
`1
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`