CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`213051Orig1s000
`
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`
`
` Recommendation: Approval
`
`
`
`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`
`
`
` NDA 213051 and 213182
`
` Review 1
`
`
`
` Drug Name/Dosage Form Rybelsus (semaglutide) tablets
`
`
`
` 3 mg, 7 mg, or 14 mg
` Strength
` Route of Administration
` Oral
`
`
`
` Rx/OTC Dispensed
` Rx
` Novo Nordisk
`
` Applicant
`
` US agent, if applicable
` -
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`SUBMISSION(S)
` REVIEWED
`
`
` Original and amendments
` (NDA 213051)
`
`
`Original and amendments
`
` (NDA 213182)
`
`
`
`
`
`
`
` DOCUMENT DATE
`
`
`
`Original submission (3/20/2019) and
`amendments (5/23/19, 6/28/19, 7/02/29,
`
` 7/05/19, 7/29/19, 8/01/19, and 8/15/19).
`
` Original submission (3/20/2019)
`
`DISCIPLINE(S)
`
` AFFECTED
`
` Quality modules
`
` 3, 1.14 and 1.11
`
`Quality modules
`
` 1.4 and 1.12.4
`
`
`
`
`
` BRANCH/DIVISION
` DISCIPLINE
`
`
` Branch II/New Drug API
`
` Drug Substance
` Branch VI/New Drug Products II
`
` Drug Product
`
` Branch II/ Inspectional
`Process/Microbiology/Facil
` Assessment/OPF
`
` ity
`
`
` Branch I/Regulatory Business
`
` Regulatory Business
` Process Management I
`
` Process Manager
`
`
`
` Application Technical Lead Muthukumar Ramaswamy Branch VI/New Drug Products II
`
` Branch VI/New Drug Products II
`
`
` Environmental Analysis
` Christopher Galliford
`
` (EA)
`
`
`
`
` Quality Review Team
`
` REVIEWER
`
` Daniel Jansen
`
` Christopher Galliford
`
` Frank Wackes
`
`
`
` Leeza Rahimi
`
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`1
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`
` Quality Review Data Sheet
`
`
`
`
`
`
`
`
`
`
` 1. RELATED/SUPPORTING DOCUMENTS
`
`
`
` A. DMFs:
`
`
`
`
`
`
`
` DMF #
`
`
`
` Type
`
`
`
` Holder
`
`
`
` Type III
`
` Item
`
` Referenced
`
`
`
`Status
`
`Date Review
`
` Completed
`
` Adequate 12/14/2012 (Craig
`
`
`
` Bertha) and NDA
`
`
`
` 213051 review for
`
` drug product
`
` (8/8/19)
`
`
`
`
`
`
`
`
` Comments
`
` LOA
`
` 1/10/2019
`
`
`
`
`
` B. Other Documents: IND, RLD, or sister applications
`
`
`
`
`
` DOCUMENT
`
`
`
` APPLICATION NUMBER
`
`
`
` DESCRIPTION
`
`
`
` 114464
`
`
`
` Semaglutide tablets
`
`
` IND
`
`
`
` 2. CONSULTS: None
`
`
`
`
`
`
` DISCIPLINE
`
`
`
` STATUS
`
`RECOMMENDATI
`
` ON
`
`
`
` DATE
`
`
`
` REVIEWER
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`
` 2
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`
`
`Executive Summary
`
`
`
`
`
`
`
`
` I. Recommendations and Conclusion on Approvability
`
`
`
`
`
`
`
`
` The recommendation from the Office of Pharmaceutical Quality (OPQ) for NDA 213051
`
`
`
` and 213182 is approval. This recommendation includes acceptable recommendation for
`
`
` the facilities listed in the application.
`
`
`Summary of Quality Assessments
`
`
`II.
`
`
`
`
`
`
`
`
`
` A. Product Overview
`
` Semaglutide is a long-acting analogue of GLP-1 molecule and is currently marketed as
`
`
`
`
`
` Ozempic (semaglutide) injection for improving glycemic control in adults with type 2
` diabetes (NDA 209637). Novo Nordisk has submitted two new drug applications (NDA
`
`
`
` 213051 and NDA 213182) for the marketing approval of Rybelsus® (semaglutide)
`
`
`
` tablets. Rybelsus® tablets are intended for the following indications:
`
`
`
`
`
`
`
`
`
`
` Glycemic control in adults with type 2 diabetes (NDA 213051).
`
`
`
`
`
`
`
` To reduce the risk of major adverse cardiovascular events in adults with type 2
`
`
`
` diabetes and established CV
`
`
`
`
` (NDA 213182).
`
`
` Rybelsus tablets will be available as 3, 7, and 14 mg tablets. Rybelsus tablets are for once
`
`daily oral administration. Each strength tablets will be available in cartons containing 3
`child-resistant blister cards of 10 tablets. Rybelsus® tablets should to be stored at
`
` temperature between 68ºF to 77ºF (20ºC to 25ºC).
`
` Semaglutide tablets are co-formulated with 300 mg of salcaprozate sodium (SNAC, a
`
`
`
`
`
`
`
`
`
`
` permeation enhancer). The isoelectric point of the semaglutide is 5.4. The peptide has a
` low solubility at pH range 2-6. Semaglutide is considered a BCS class 4 molecule (low
`
`
` permeability and low solubility). It is hypothesized that SNAC facilitates the oral
`
`
`
`
` absorption of semaglutide in stomach either by transiently increasing the transcellular
`
`
` permeability in gastric epithelium or through buffering action on the local environment
`
`
` near the site of action to provide a high pH and thereby protecting the semaglutide from
`
`
`
`degradation.
`
` All CMC information necessary to support NDA 213182 was cross-referenced to
`
`
` Module 2 and 3 of NDA 213051. Therefore, the CMC review provided for NDA 213051
`
`
` was used to make the OPQ recommendation for NDA 213182.
`
`
`
` Proposed Indication(s) including Intended Patient
` Population
`
`
` Duration of Treatment
`
` Maximum Daily Dose
`
`Glycemic control and CV risk
`
`
` reduction; Refer to CTDL memo
` Refer to CTDL memo
`
`
`
` 14 mg
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`
` 3
`
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
` Not applicable
`
` QUALITY ASSESSMENT
`
`
`
`
` Alternative Methods of Administration
`
`
`
`
`
`
`
`
` B. Quality Assessment Overview
`
`
`
` Drug Substance
`
`
`
`
` Semaglutide is a modified analogue of human GLP-1 [7-37] peptide. Compared to the
` amino acid sequence of GLP-1 [7-37] peptide, the semaglutide peptide sequence
`
`
` contains two amino acid substitutions (Ala8 to Aib8 (2-aminoisobutyric acid), Lys34
`
` to Arg34) and a modification at lysine 26 side chain with fatty diacid moiety. The
`
`
`
` manufacturing process for semaglutide drug substance consists of
`
`
`
`
`
`
`
`
` The drug
`
`
`substance batches produced from the proposed drug substance manufacturing process
`
` (process III) was used in Phase 1 and 3 clinical studies.
`
`
`
`
`
`
` The CMC information for drug substance was reviewed by Dr. Daniel Jansen. Dr.
` Jansen’s review concluded that the NDA contains adequate information on drug
`
`
`
` substance characterization and provides adequate manufacturing process description,
` process controls, and drug substance specification for manufacturing consistent
`
`
`
`
`
` quality drug substance. Based on stability data review, a shelf-life of months is
`
`
`
`
`granted for the semaglutide drug substance when stored
`
`
`
`
`
`For additional
`
` details, please refer to CMC review for drug substance in Panorama dated 5/28/2019.
`
` Drug Product
`
` Semaglutide tablets will be available in 3 strengths (3 mg, 7 mg, or 14 mg per tablet),
`
`
`as white to light yellow oval shaped tablets debossed with “novo” on one side and on
`
`
`
`
` the other side with 3 or 7 or 14. The tablets are packaged in blister cards
`
`
`
` Each blister card will contain 10 tablets. Blister packs are further
`
`
` packaged in cartons (3 per carton).
`
` Each strength tablet contains 300 mg of salcaprozate sodium. Besides salcaprozate
`
`
`sodium (SNAC), the tablets contain micro-crystalline cellulose
`,
`Povidone
`, and magnesium stearate
`. Salcaprozate is
`
`
` a novel excipient. All other excipients present in the drug product are USP grade
`
` excipients.
`
` Excipient related information including manufacturing and control information for
`
`
`salcaprazoate was reviewed by drug product reviewer. His review concluded that the
`
`
`
` manufacturing and control information for SNAC and other excipients are adequate.
` The proposed specifications for salcaprozate include
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`4
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` QUALITY ASSESSMENT
`
`
`
`
`in the product is supported non-clinical and clinical studies.
`
`
` Rybelsus tablet manufacturing process uses
`
`
`
`
`
`
`
`
`
` . Salcaprazoate use
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The composition of the product, the process used for manufacturing the drug product
`batches and the packaging system used for the drug product in phase 3 clinical studies
`are the same as that proposed for commercial use. The manufacturing process flow
`information is aligned with the proposed master batch record. The batches used in
`
` clinical and non-clinical studies are identified in the application.
`
` The applicant’s control strategy for producing acceptable quality drug product is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Dr. Frank
`
`
` Wackes reviewed the manufacturing process and control information and facility
`
`
`
`
`
` compliance information. OPF process review includes risk assessment for
` manufacturing process control and its relationship to drug product critical quality
`
`
` attributes. OPF review concluded that the process and facilities information provided
` in the NDA is adequate. Please refer to process/facilities review in Panorama dated
`
`
` 7/30/2019.
`
` The applicant performed a risk assessment for elemental impurities per ICH Q3D and
`
`
` provided justification for not including routine elemental impurities testing in the
` product. In addition, Dr. Ramaswamy performed a risk assessment for the finished
`
`
` product critical quality attributes and his assessment concluded that the final quality
`
`
` risk is low for the proposed product (Refer to Appendix I).
`
` The finished product specification was finalized by the drug product and
`
`
`
`
` biopharmaceutics reviewers. The drug product is tested for visual appearance, identity
`of semaglutide by RPHPLC and peptide mapping, assay, uniformity of dosage units,
`HMWP, impurities
`, and sum of
`
`
`
`
` and dissolution. The quality attributes
`impurities), microbial purity,
` considered for inclusion in the drug product specification are in alignment with the
`
`
`
` attributes recommended for oral dosage forms under USP <2> Oral drug products –
`
`
` product quality tests. Please refer to Dr. Galliford’s drug product review dated 8/9/19
`
` for additional information.
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`
` 5
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` QUALITY ASSESSMENT
`
`
`
`
`
`
`
` A dissolution test is proposed for measuring the quality of semaglutide tablets.
`
`Dissolution acceptance criteria proposed for the product is based on data from
`
`
` primary stability batches. Dr. Vincent Li’s reviewed the dissolution method and he
`
` proposed dissolution acceptance criteria. Per FDA recommendation, the applicant has
`
`
` agreed to use an interim dissolution specification of Q = % semaglutide at 45
`
`
` minutes for all strength tablets up to a period of one year and committed to provide
`
`
`
`
` additional dissolution data
` in the first annual report. Dr. Li’s recommendation for this NDA is adequate.
`
`
`Please refer to biopharma review dated 8/9/19 in Panorama and NDA amendment
`
`dated 8/16/19 for additional information.
`
`
`
` The applicant sought exemption from environmental impact analysis per 21CFR
`
`25.31(a) as the action on this NDA does not increase the use of semaglutide. Dr.
` Galliford reviewed the request and granted categorical exclusion from submitting
`
`environment assessment. Please refer to drug product review dated 8/9/19 in
`
` panorama for additional information.
`
`Expiration Date & Storage Conditions: Drug product is light sensitive. Therefore,
` storage of the product in blister packaging is warranted. The application contains 6
`
`
`
`
` month accelerated stability (40°C/75% RH) and 24 moths of intermediate/ long-term
` storage stability data (25°C/60% RH and 30°C/75% RH) for 3 primary stability
`
`
`
`
`
`
`
` batches manufactured at pilot scale. Stability information was reviewed by drug
`
`
`
` product reviewer and concluded that the product is stable in the proposed packaging.
`
`
`
`
`
`
` A shelf-life of 24 months is granted when stored at 68 -77°F ((20°-25°C) in original
`
`
`
`packaging. Excursions permitted to 59°-86°F (15°-30°C) [see USP Controlled Room
`
`
`
` Temperature]. Do not freeze. Please refer to drug product review dated 8/9/19 in
` Panorama for additional information.
`
`
`
` Container and Carton Label Review: Drug product reviewer completed review of
`
`container and carton label. Dosage form, strength, established name, NDC #, Lot
`
` #/expiry, and storage conditions are adequately described in the carton and container
` label, which meets relevant regulatory requirements for labeling. Refer to drug
`
`
`
` product review for a copy of the label.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`OVERALL ASSESSMENT AND SIGNATURES:
`
` OPQ CMC review concludes that there are no outstanding deficiencies related to drug
`
`
`
`substance, drug product, process, facilities, biopharmaceutics, environmental analysis,
`
`
`
` container and carton label. OPQ overall recommendation for NDA 213051and 213182 is
`
` approval.
`
`
`
`
`
`
`
`
` Muthukumar Ramaswamy, Ph.D. 8/19/2019
`
`
`
` Application Technical Lead Name and Date:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`6
`
`
`
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` From Initial Risk Identification
`
`
`
` QUALITY ASSESSMENT
`
`
`
`
`Attachment I: Final Risk Assessments
`
`
`
`
` Review Assessment
`
`
` Risk Mitigation
` Approach
`
`
`
`
`
`
`
`
`
` Attribute/ CQA Factors that can impact the Initial Risk
`
`
`
`
`
`
` Ranking
`
`
` CQA
`
`
`
` Final Risk
`
`
` Ranking
`
`
`
`
` Lifecycle Considerations/
` Comments
`
`
`
`
`
`
` Drug content
` (potency)
`
`
`
`
` Formulation, process (tablet
`
` weight), container/
`
` stability/Method
`
`
`
`
`
`
`
`
` Dose Uniformity Formulation, process (tablet
` weight), container/ stability/
`
`
`
`
` Method
`
`
`
` Particle Size
` Distribution of API
`
`
`
`
`
`
`
` Formulation, process
`
`
`
`
`
` Formulation, process
`
`
`
`
`
` Formulation, stability,
` Process, Container closure
`
`
`
`
`
`
` Hydrophobic and
` hydrophilic,
`
` Impurities/ HMWP
`
`
`
`
`
`
` H
`
`
`
` H
`
`
`
` M
`
`
`
` M
`
`
`
` H
`
`
`
` Acceptable
`
`
`
` None
`
`
`
` Acceptable
`
`
`
`
`
` Acceptable
`
`
`
` none
`
`
`
` Acceptable
`
`
`
` None
`
`
`
` Acceptable
`
`
`
` none
`
` Acceptable
`
` none
`
`
`
` Appearance
`
`
` Formulation, process,
` Container closure, stability
`
`
`
`
`
`
`
`
`
` Microbial load
`
`
`
`
`
` Container closure
`
`Proces
`
`
`
` Salcaprozate Content Formulation, process and
`
`
`
` product performance
`
`
`
`
`
`
`
`
`
` In vitro dissolution
`
`
`
`
` Formulation, process,
` incoming materials
`
`
`
`
`
` Salcaprozate
`
`
`
` Formulation, process,
`
` product performance
`
`
` Microbial
`
`
` contamination
`
`
` Formulation, process,
` packaging
`
`
`
`
`
`
`Reference ID: 4480609
`Reference ID: 4497378
`
`
`
`
`
`
`
`
` Acceptable
`
`
`
` none
`
`
`
` Acceptable
`
`
`
` none
`
`
`
` Acceptable
`
`
` An-interim dissolution
`
`
` specification of Q= % at 45
`
`
` min is proposed. The applicant
`
`
`
` committed to provide
`
`
`
` dissolution data for additional
`
`
`
` batches in the first annual
`
`
`
`
` report.
`
`
`
`
`
`
`
`
` Acceptable
`
`
`
` none
`
`
`
` Acceptable
`
`
`
` None
`
`
`
` H
`
`
`
` H
`
`
`
` H
`
`
`
` H
`
`
`
` H
`
`
`
` M
`
`7
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Muthukumar
`Ramaswamy
`
`Digitally signed by Muthukumar Ramaswamy
`Date: 8/19/2019 12:40:11PM
`GUID: 508da7210002a0c0870017f6c83398f4
`
`
`
`Reference ID: 4480609
`Reference ID: 4497378
`
`
`

`

`
`
`
`
` Drug Substance Name
`
` NDA Number
` Assessment Cycle Number
`
` DMF Number (If
`
` Applicable)
` DMF Status
`
` Applicant Name
`
` DMF Holder
`
`
`
`
`CHAPTER I: DRUG SUBSTANCE
`
`
`
`
`
` Semaglutide
`
` 213051
`
` 1
` n/q
`
`
` Adequate
`
` Novo-Nordisk
`
`
` n/a
`
`
`
`
`
` Assessment Recommendation: Adequate
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`
`
`
`
`
`
`(b) (4)
`
`28 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`
`
` REGIONAL INFORMATION
`
` Comparability Protocols
`
`
`
`
`
`
` Assessment: N/A
`
`
`
`
`
`
` Post-Approval Commitments
`
`
`
`
` Assessment: N/A
`
`
`
`
`
`
` Lifecycle Management Considerations
`
` None
`
`
` DRUG SUBSTANCE LIST OF DEFICIENCIES
`
` None
`
`
`
`
`
`
`
`
` Primary Drug Substance Assessor Name and Date:
`
` Secondary Assessor Name and Date (and Secondary Summary, as needed):
`
`
`
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`(b) (4)
`
`

`

`Daniel
`Jansen
`
`Su (Suong)
`Tran
`
`Digitally signed by Daniel Jansen
`Date: 5/28/2019 03:42:46PM
`GUID: 5c87e2d5004165375e1d69fdaafc7515
`
`Digitally signed by Su (Suong) Tran
`Date: 5/28/2019 04:04:43PM
`GUID: 508da71f00029ec8b75e233f12b15339
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`
`
`
`ASSESSMENT OF THE DRUG PRODUCT
`
`DRUG PRODUCT
`2.3.P
`
`This section of the review includes evaluation of data submitted in the original NDA
`(03/20/2019), and subsequent NDA amendments pertaining to drug product quality and
`labeling, submitted through 08/01/2019. From the perspective of drug product reviewer, the
`submitted materials are adequate to support the marketing of the drug product.
`
`
`Description and Composition of the Drug Product
`2.3.P.1
`
` Semaglutide is a glucagon like peptide-1 (GLP-1) analog for the treatment of type 2 diabetes.
`
`
` The semaglutide drug product presentations are white to light yellow oval shaped tablets (7.5
`
`mm x 13.5 mm). The tablets are debossed with a unique identification depending on the
`
`strength:
`
` 3 mg tablets: “3” is debossed on one side of the tablet and “novo” on the other side.
`
`
`
` 7 mg tablets: “7” is debossed on one side of the tablet and “novo” on the other side.
`
`
`
` 14 mg tablets: “14” is debossed on one side of the tablet and “novo” on the other side.
`
`
`
`
`The tablet weight is around 0.4 g and depends on the strength. The quantitative composition
`
`
` of the drug product in each strength is as follows:
`
`
`
`The proposed proprietary name is Rybelsus. When approved, the full name of the drug
`product will be: Rybelsus™ (semaglutide) tablets 3 mg, 7 mg or 14 mg.
`
`
`
`
`Reviewer’s Assessment: Adequate.
`Adequate information and data are provided in support of drug product composition. The
`API, semaglutide, is manufactured Novo Nordisk A/S, Hallas Allé 1, Kalundborg, Sjælland
`
`4400, Denmark.
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`1
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`2.3.P.2 Pharmaceutical Development
`The semaglutide drug product is a tablet formulation containing 3, 7 or 14 mg of the active
`pharmaceutical ingredient semaglutide. The corresponding injection formulation, Ozempic®
`(NDA 209637), was approved by the agency on Dec 5, 2017. Therefore, this application is a
`new formulation of the same API. The tablets are uncoated immediate release tablets
`
`intended for oral administration. The drug product compositions for each strength are
`reproduced from the application below:
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`2
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`29 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
` I. Review of Common Technical Document-Quality (Ctd-Q) Module 1
`
`
`Labeling & Package Insert
`
`
`1. Package Insert
`
`
`
`
`
`
`
`
`Reference ID: 4480609
`Reference ID: 4497378
`
`
`32
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`
`
`(a) “Highlights” Section (21CFR 201.57(a))
`
`Item
`
`
`Reviewer’s Assessment
`
`
`Adequate accepted by
`
`DMEPA
`
`
`Adequate
`
`Adequate
`
`
`Adequate
`
`Information
`Provided in NDA
`Product title, Drug name (201.57(a)(2))
`
`Rybelsus™
`
`Proprietary name
`and established
`(semaglutide
`
`
`name
`tablets), 3, 7 or 14
`
`mg.
`
`for
`Tablets
`
`administration.
`
`Not required
`
`oral
`
`Dosage form, route
`
`of administration
`Controlled drug
`substance symbol
`(if applicable)
`
`Dosage Forms and Strengths (201.57(a)(8))
`
`A concise summary
`Tablets for oral
`administration in 3,
`of dosage forms
`
`and strengths
`7 or 14 mg
`strengths.
`
`
`
`Conclusion: Adequate
`
`
`
`
`
`
`
`
`
`Reference ID: 4480609
`Reference ID: 4497378
`
`
`33
`
`
`

`

`
`
`
`
`
`QUALITY ASSESSMENT
`
` (b) “Full Prescribing Information” Section
`
`# 3: Dosage Forms and Strengths (21CFR 201.57(c)(4))
`Rybelsus™ (semaglutide tablets), 3, 7 or 14 mg.
`
` Information Provided in NDA Reviewer’s Assessment
`
`Item
`Available dosage forms
`Rybelsus tablets are available as:
`
`
`Adequate
` 3 mg, white
`to
`light
`
`
`shaped
`yellow,
`oval
`debossed with “3” on
`one side and “novo” on
`
`the other side.
`
`to
`light
` 7 mg, white
`
`shaped
`yellow,
`oval
`debossed with “7” on
`
`one side and “novo” on
`the other side.
`
` 14 mg, white to light
`
`shaped
`yellow,
`oval
`debossed with “14” on
`
`one side and “novo” on
`the other side.
`3, 7 or 14 mg.
`
`
`
`Adequate
`
`
`Adequate
`
`Strengths: in metric system
`
`A description of the
`identifying characteristics of
`the dosage forms, including
`shape, color, coating,
`scoring, and imprinting,
`when applicable.
`
`Rybelsus tablets, for oral use,
`contains semaglutide, a GLP-1
`receptor agonist. The peptide
`
` backbone is produced by yeast
`
`fermentation.
`The
`main
`
`
`of
`mechanism
`protraction
`semaglutide is albumin binding,
`facilitated by modification of
`position 26
`lysine with
`a
`hydrophilic spacer and a C18
`fatty
`di-acid.
`semaglutide
`Furthermore,
`is
`
`modified in position 8 to provide
`stabilization against degradation
`by
`the
`enzyme
`dipeptidyl­
`
`peptidase 4 (DPP-4). A minor
`
`modification was made
`in
`the
`position 34
`to
`ensure
`
`attachment of only one fatty di­
`acid. The molecular formula is
`
` C187H291N45O59 and the molecular
`weight is 4113.58 g/mol.
`Semaglutide is a white to almost
`
`white hygroscopic powder. Each
`tablet of Rybelsus contains 3 mg,
`7 mg or 14 mg of semaglutide
`
`34
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`

`

`
`
`
`
`Conclusion: Adequate
`
`
`QUALITY ASSESSMENT
`
`inactive
`following
`the
`and
`ingredients: salcaprozate sodium,
`microcrystalline
`cellulose,
`
`povidone
`and
` magnesium
`stearate.
`
`
`
`
`
`
`Reference ID: 4480609
`Reference ID: 4497378
`
`
`35
`
`
`

`

`QUALITY ASSESSMENT
`
`#11: Description (21CFR 201.57(c)(12))
`Rybelsus tablets, for oral use, contains semaglutide, a GLP-1 receptor agonist. The
`
` peptide backbone is produced by yeast fermentation. The main protraction
`mechanism of semaglutide is albumin binding, facilitated by modification of position
`26 lysine with a hydrophilic spacer and a C18 fatty di-acid.
`
`
`
`
`Furthermore, semaglutide is modified in position 8 to provide stabilization against
`degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification
`
`was made in position 34 to ensure the attachment of only one fatty di-acid. The
`
`molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol.
`
`Semaglutide is a white to almost white hygroscopic powder. Each tablet of Rybelsus
`contains 3 mg, 7 mg or 14 mg of semaglutide and the following inactive ingredients:
`salcaprozate sodium, microcrystalline cellulose, povidone and magnesium stearate.
`
`
`
`
`Reviewer’s Assessment
`
`
`
`
`Adequate
`
`
`Adequate
`
`
`Adequate
`
`
`
`Adequate
`
`
`
`Adequate
`
`
`Adequate
`
`
`Adequate
`
`
`Adequate
`
`
`Item
`
`Proprietary name and established
`
`name
`
`Dosage form and route of
`
`administration
`Active moiety expression of
`
`strength with equivalence
`statement for salt (if applicable)
`Inactive ingredient information
`(quantitative, if injectables
`21CFR201.100(b)(5)(iii)), listed
`by USP/NF names.
`Statement of being sterile (if
`applicable)
`Pharmacological/ therapeutic
`class
`Chemical name, structural
`
`formula, molecular weight
`
`If radioactive, statement of
`important nuclear characteristics.
`
`Other important chemical or
`
`Information Provided in
`NDA
`
`
`Provided
`
`
`Provided
`
`
`Provided
`
`
`Provided
`
`
`Not required
`
`Provided
`
`
`Provided
`
`
`Not required
`
`Provided
`
`
`36
`
`
`
`
`
`
`
`
`Reference ID: 4480609
`Reference ID: 4497378
`
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`
`
`Adequate
`
`physical properties (such as pKa,
`solubility, or pH)
`
`Conclusion: Adequate
`
`
`
`
`#16: How Supplied/Storage and Handling (21CFR 201.57(c)(17))
`Store in the original package to protect from light and moisture. Store at 68°-77°F (20°-25°C);
`
`excursions permitted to 59°-86°F (15°-30°C) [see USP Controlled Room Temperature]. DO NOT
`FREEZE.
`
`
`
` Information Provided in NDA Reviewer’s Assessment
`
`3, 7 or 14 mg tablets
`
`
`Adequate
`
`
`Adequate
`
`Item
` Strength of dosage form
`
`
`
`Available units (e.g., bottles
`of 100 tablets)
`
`Identification of dosage
`forms, e.g., shape, color,
`coating, scoring,
`imprinting, NDC number
`
`Special handling (e.g.,
`protect from light, do not
`
`freeze)
`Storage conditions
`
`
` Rybelsus® is available in blister
`
`packs of 10 tablets of 3, 7 and 14
`
`mg strengths.
`
`Provided
`
`
`Provided
`
`
`Provided
`
`
`
`Adequate
`
`
`
`Adequate
`
`
`
`Adequate
`
`
`
` Manufacturer/distributor name listed at the end of PI, following Section #17
`
`
`
`
`Item
`Manufacturer/distributor name
`
`(21 CFR 201.1)
`
`
`
`Conclusion: Adequate
`
`
`
`Information Provided in NDA Reviewer’s Assessment
`Manufactured by:
`
`
`Adequate
`Novo Nordisk A/S
`DK-2880 Bagsvaerd
`Denmark
`
`
`
`
`
` 2. Container and Carton Labeling
`
`
`
`
` 1) Immediate Container Label
`
`37
`
`
`
`
`
`
`
`
`Reference ID: 4480609
`Reference ID: 4497378
`
`
`3 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS)
`immediately following this page
`
`

`

`
`
`
`Item
`Proprietary name,
`established name (font size
`and prominence (21 CFR
`201.10(g)(2))
`
`Strength (21CFR
`201.10(d)(1); 21.CFR
`201.100(b)(4))
`
`Route of administration
`21.CFR 201.100(b)(3))
`Net contents* (21 CFR
`201.51(a))
`Name of all inactive
`ingredients (; Quantitative
`ingredient information is
`required for injectables)
`
`21CFR 201.100(b)(5)**
`Lot number per 21 CFR
`
`201.18
`Expiration date per 21 CFR
`201.17
`
`“Rx only” statement per 21
`CFR 201.100(b)(1)
`Storage
`(not required)
`
`
`NDC number
`(per 21 CFR 201.2)
`(requested, but not required
`for all labels or labeling),
`also see 21 CFR
`
`207.35(b)(3)
`
`Bar Code per 21 CFR
`201.25(c)(2)***
`
`Name of
`manufacturer/distributor
`(21 CFR 201.1)
`Warnings
`
`QUALITY ASSESSMENT
`
`Comments on the Information Provided in
`NDA
`Rybelsus® 3, 7, 14 mg tablets.
`
`
`Conclusions
`Adequate
`
`3, 7 or 14 mg tablets
`
`oral
`
`3, 7 or 14 mg tablets
`
`
`Provided
`
`Space is provided
`
`Space is provided
`
`Provided
`
`
`Provided
`
`
`
`
`
`
`Provided
`
`Provided
`
`
`
`
`Provided
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`
`Store in the original package to protect from
`light and moisture. Store at 68°-77°F (20°­
`25°C); excursions permitted to 59°-86°F (15°­
`
`30°C) [see USP Controlled Room
`Temperature]. DO NOT FREEZE.
`
`*21 CFR 201.51(h) A drug shall be exempt from compliance with the net quantity declaration
`required by this section if it is an ointment labeled ‘‘sample’’, ‘‘physician’s sample’’, or a
`
`
`substantially similar statement and the contents of the package do not exceed 8 grams.
`**For solid oral dosage forms, CDER policy provides for exclusion of “oral” from the container
`label
`
`Adequate
`
`
`
`
`
`Reference ID: 4480609
`Reference ID: 4497378
`
`
`41
`
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`**Not required for Physician’s samples. The bar code requirement does not apply to prescription
`
` drugs sold by a manufacturer, repacker, relabeler, or private label distributor directly to patients,
`but versions of the same drug product that are sold to or used in hospitals are subject to the bar
`
`code requirements.
`
`Conclusion: Adequate
`
`
`
`
`
` 2) Carton Labeling
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4480609
`Reference ID: 4497378
`
`
`42
`
`
`(b) (4)
`
`2 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS)
`immediately following this page
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`Comments on the Information Provided in
`NDA
`Rybelsus® 3, 7, 14 mg tablets.
`
`
`Item
`Proprietary name, established
`name (font size and prominence
`(FD&C Act 502(e)(1)(A)(i),
`FD&C Act 502(e)(1)(B), 21 CFR
`
`201.10(g)(2))
`Strength (21CFR 201.10(d)(1);
`21.CFR 201.100((d)(2))
`
`Net contents (21 CFR 201.51(a))
`
`Lot number per 21 CFR 201.18
`Expiration date per 21 CFR
`201.17
`
`Name of all inactive ingredients
`(except for oral drugs);
`Quantitative ingredient
`information is required for
`injectables)[ 201.10(a),
`
`21CFR201.100(d)(2)]
`
`3, 7 or 14 mg tablets
`
`3, 7 or 14 mg tablets
`Space is provided
`
` Space is provided
`
` Provided
`
`
`
`
`Sterility Information (if
`applicable)
`“Rx only” statement per 21 CFR
`201.100(d)(2), FD&C Act
`503(b)(4)
`Storage Conditions
`
`
`Space is provided
`
`Provided
`
`
`Provided
`
`
` NDC number
`
`(per 21 CFR 201.2)
`
`(requested, but not required for
`all labels or labeling), also see 21
`
`CFR 207.35(b)(3)
`
`
`
` Provided
`
`Bar Code per 21 CFR
`201.25(c)(2)**
`Name of
`manufacturer/distributor
`“See package insert for dosage
`
`information” (21 CFR 201.55)
`“Keep out of reach of children”
`(optional for Rx, required for
`OTC)
`
`Route of Administration (not
`required for oral, 21 CFR
`201.100(d)(1) and (d)(2))
`
`
`
`Provided
`
`
`
`
` Provided
`
`Provided
`
`Keep out of reach of children
`
` Not required
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`45
`
`Conclusions
`Adequate
`
`Adequate
`
`Adequate
`Adequate
`Adequate
`
`Adequate
`
`
`Adequate
`
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`

`

`QUALITY ASSESSMENT
`
`
`
`
`
`Conclusion: Adequate.
`
`
`
`
` OVERALL ASSESSMENT AND SIGNATURES: LABELING
`
`
`
`
`
`Reviewer’s Assessment and Signature:
`ADEQUATE
`
`
`
`Secondary Review Comments and Concurrence:
`I concur with the reviewer’s assessment.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`46
`
`

`

`Christopher
`Galliford
`
`Muthukumar
`Ramaswamy
`
`Digitally signed by Christopher Galliford
`Date: 8/21/2019 12:42:41PM
`GUID: 56324afd003b6374e3a936887dea798c
`
`Digitally signed by Muthukumar Ramaswamy
`Date: 8/21/2019 12:43:45PM
`GUID: 508da7210002a0c0870017f6c83398f4
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`

`

`
`
`
`
`
`
`
` Application ID
`
`
`
`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`MANUFACTURING INTEGRATED ASSESSMENT
`
`
`
`
`
`
` NDA 213051 & NDA 213182
`
` Priority Review based on Tropical Disease Voucher
`
`
` semaglutide
` Drug Product Name
`
` 3 mg, 7 mg, 14 mg
`
` Strengths
`
`
` tablet
` Dosage Form
`
`
` Administration Route oral
`
`
` [Same product and strengths, but, 2 different indications]
`
` Indication
`
`
` NDA 213051:
`
`
`
`
`
` As an adjunct to diet and exercise to improve glycemic control
`
` in adults with type 2 diabetes mellitus
`
`
`
` NDA 213182:
`
`
` To reduce the risk of major adverse cardiovascular events
`
`
` (cardiovascular death, nonfatal myocardial infarction or non­
`
`
` fatal stroke) in adults with type 2 diabetes mellitus and
`
`
`
`
`
` established cardiovascular disease
`
`
`
` Novo Nordisk Inc.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Applicant Name
`
`
`
`
`
`
` I. Manufacturing Summary
`
`
`
`
`
` Facility Assessment Recommendation: Adequate
` Process Assessment Recommendation: Adequate
`
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`(b) (4)
`
`(b) (4)
`
`36 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`
` 2. Pre-Approval Inspection Summary
`
` Not Applicable
`
`
`
`
`
`
`
`
`
`
`
`
`
` (over)
`
`
`
`Page 38 of 40
`
`
`
`
`
`OPF NDA Manufacturing Integrated Assessment Version January 31, 2019
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
` QUALITY ASSESSMENT
`
`
`
` IV. Testing Facilities / Primary Packaging Facilities
`
`
`
`
`
`
`
` 1. List of Testing Facilities
`
`
`
`
`
` The following commercial DS/DP Control Testing Laboratories have been proposed by
`
`
`
` the applicant to support external testing function of the pending drug product. The
`
`
`
`
`
`
`
`
`
`
` facilities proposed below, unless noted otherwise, are within compliance standards and
`
`
`
`
`
`
`
` have the ability to perform the function and responsibilities outline in the application
`
`
`
`
`
`
`
`
`
`
`
` following assessment:
`
`
` Facility Name/FEI
`
`Novo Nordisk A/S –
`
`
`
` FEI 3003131673
`
`
`
`
`
`
`
` Responsibilities
`
`1. Quality control
`
`
`
`
` Previous OPF evaluation (Link)
`
`
` Relevant and acceptable.
`
`
`
`
`
`
`
`
`
`
`chemical/physical
`
` testing
` 2. Quality control of raw
`
` materials
` 3. Storage of raw
`materials,
`
`
` and drug substance
`4. Quality control of DP
`excipients: Chemical
`
` testing
`5. Quality control of
`
` primary packaging
`materials: Chemical
`
` testing
`6. Storage of DP
`
` excipients
`
`
`
`
` 2. Facility Level Evaluation of Commercial DS/DP Testing Facility
`
`
` Not Applicable
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3. Facility Level Evaluation of Primary Packaging Facility
`
`
` Not Applicable
`
`
`
`
`
`
`
`
`
`
`
` 4. Pre-Approval Inspection Summary
`
` Not Applicable
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4480609Reference ID: 4497378
`
`Page 39 of 40
`
`
`
`
`
`OPF NDA Manufacturing Integrated Assessment Version January 31, 2019
`
`
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`
`
`
`
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` QUALITY ASSESSMENT
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` V. List of Outstanding Information Request/Defi