CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`209637Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`QUALITY REVIEW
`
`Recommendation:
`
`APPROVAL
`
`(including the Facility Review/Overall Manufacturing Inspection Recommendation)
`
`NDA 209637
`
`Review #1
`
`Review Date (see last page)
`
`semaglutide injection
`m 1.34 mg/mL (as 2 mg/l .5 mL per pen injector)
`subcutaneous injection
`Rx
`Novo Nordisk
`
`6/23/17
`Elizabeth Bean/Erika Pfeiler
`
`SUBMISSION S REVIEWED
`
`__
`0007
`0014
`0017
`0027
`
`DOCUMENT DATE
`12/5/16
`3/1/17
`5/1/17
`5/8/17
`
`DISCIPLINE
`
`0 uali
`REVIEWER
`
`' Review Team
`
`DIVISION/OFFICE
`
`Regulatory Business
`
`Anika Lalmansingh
`
`uong (Su) Tran
`0e Leginus/Donna Chn'smer
`Muthu Ramaswamy/Danae Christodoulou
`Drug Product
`w Chaoying Ma/Yong Hu
`Facility
`Vidya Pai/Juandn'a Williams
`Christopher Brown
`
`Regulatory Business Process
`Management I/OPRO
`New Drug Products II/ONDP
`New Drug API/ONDP
`New Drug Products II/ONDP
`Process Assessment lI/OPF
`
`Inspectional Assessment/OFF
`CDRH Compliance
`
`Microbi0103Assesment/OPF
`
`Quality Review Data Sheet
`1. RELATED/SUPPORTING DOCUNIENTS:
`
`A. DNIFs: Adequate
`B. Other Documents: not applicable
`2. CONSULTS: CDRH Compliance (recommendation is included in the OPQ
`Facility review; see separate review in DARRTS)
`
`

`

`QUALITY REVIEW
`
`Executive Summary
`
`Recommendation and Conclusion on Approvability
`1.
`The final OPQ recommendation is for Approval, including the overall manufacturing
`inspection recommendation.
`
`H.
`
`Summary of Quality Assessment
`
`A. Product Overview
`
`This is a 505(b)(l) NDA for semaglutide, a New Molecular Entity.
`Semaglutide is an analog of the 7-37 peptide fragment of the human glucagon-like
`peptide-l (GLP-l).
`The drug product is a clear solution for subcutaneous injection, 1.34 mg/mL,
`packaged in a 1.5 mL (or 2 mg semaglutide) cartridge pre—assembled in a multi-dose
`single-patient pen injector.
`
`Alternative Methods of Administration
`
`Pro u osed Indication s
`
`Maximum Dail Dose
`
`[not finalized by GRMP goal; see CDTL’s memo]
`[not finalized by GRMP goal; see CDTL’s memo]
`[not finalized by GRMP goal; see CDTL’s memo]
`
`B. Quality Assessment Overview
`
`Drug Substance
`Semaglutide is an analog of human GLP-l(residues 7-37) and acts as a GLP-1
`receptor agonist. The drug substance is
`(m4)
`chemical
`
`modifications (attachment of octadecanedioic acid via linkers to Lysine 26, and
`change in position 8 from Alanine to 2-aminoisobutyric acid).
`
`Hie molecular formula for semaglutide is Cm H391 N45 059 and the molecular mass is 4113.6 Da.
`
`7
`0
`1o
`Nwefiwm's o v
`
`20
`H
`O
`30
`37
`s v L\-:e>@x9xg@~\)l®®w A w L v R o R s
`O
`\ Ly.
`
`26
`
`0H
`
`O
`
`GIu—spacer
`
`H
`J‘L A O 7A A .NH
`N A /'\ O
`V O V v ‘N’ \/ IV 0 W
`H
`0
`
`Hon" NH
`
`LIB-octadecanemolc acbd
`
`O
`
`

`

`QUALITY REVIEW
`
`The drug substance diflers from human GLP-l by a substitution of lysine at
`position 34 by arginine and the two chemical modifications described above,
`which are designed to slow the plasma degradation of the molecule and decrease
`its renal clearance, prolonging its half—life. Semaglutide also differs from
`liraglutide (an approved product by the same applicant) in that liraglutide has a
`different fatty acid and linkers attached to Lysine 26 and is not modified at
`position 8.
`
`The drug substance manufacturing process consists
`
`(m4)
`
`Manufacturing
`Process 6R produced drug substance batches used in product batches for the phase
`3 clinical studies and primary stability studies, and the same process has been
`validated as the commercial process. Adequate information on the manufacturing
`process, including cell banking and comparability of earlier manufacturing
`processes, is provided in the NBA. The manufacturing process
`
`(5x4)
`
`mu) peptide,
`Characterization of the drug substance is standard for a
`including the following testing: peptide mapping, circular dichroism, mass
`spectrometry, potency by a cell-based bioassay (cAMP—sensitive luciferase
`reporter gene assay and BHK cells), isoelectric focusing, solubility, pH, UV
`spectroscopy, dynamic water sorption, RP- and SE- HPLC, visual appearance,
`and a potency—content by HPLC correlation.Characterization of peptide—related
`impurities and degradants is provided, including the relative bioactivities (but)
`
`The drug substance specification includes attributes standard for this type of drug
`substance (
`mm). The same bioassay used for characterization is
`included in the drug substance specification. Impurities are grouped by their
`hydrophilic and hydrophobic properties, with limits based on nonclinical and
`clinical batches. The specification includes high molecular weight proteins and
`host cell proteins;
`(law). The
`drug substance is
`
`"'""
`
`The long term storage is at «no °C, in a
`life (not retest) of 8 months. The drug substance is sensitive to
`M (4)
`
`(mo, with a shelf
`(m4)
`
`Drug Product
`The drug product is a clear solution for subcutaneous injection, 1.34 mg/mL,
`packaged in a 1.5 mL (or 2 mg semaglutide) cartridge pre-assembled in a multi—
`dose single-patient pen injector. The commercial formulation is the same as that
`used in the pivotal phase 3 studies and primary stability studies.
`
`

`

`QUALITY REVIEW
`
`Excipients: disoldium phosphate dihydrate (1.42 mg/mL), propylene glycol (14.0
`mg/mL), phenol (5.5 mg/mL), water for injection, and hydrochloric acid and
`sodium hydroxide for pH adjustment (pH 7.4). All excipients are compendial.
`There is no novel excipient, and there is no human/animal—derived excipient. The
`formulation has an
`(m4)
`
`[4
`
`The drug product manufacturing process consists
`
`(but)
`
`the same process has been validated as the commercial process.
`Sufficient information is provided to demonstrate sterility assurance. Reference is
`made to DMF M9 for information on the
`(m4) information; this DMF
`is currently adequate. The phase 3 product batches were manufactured at the
`commercial site, using the commercial process with minor differences.
`Reference is made to the CDRH review of the pen injector-cartridge assembly and
`other device-related manufacturing information.
`
`The regulatory drug product specification is adequate based on the supporting
`release and stability data and ICH guidelines for this type of dosage form. It does
`not include testing for biological activity because the assay method by HPLC is
`found to be adequately correlated with potency (by the cell-based bioassay of the
`drug substance). Same as for the drug substance impurities, degradants are
`grouped by their hydrophilic and hydrophobic properties, with limits based on
`nonclinical and clinical batches. The specification includes high molecular weight
`proteins and
`(mu) content.
`(m4)
`meets the compendial criteria for antimicrobial efl'ectiveness.
`and is not part of the drug product specification.
`Reference is made to the CDRH review of dose accuracy, which is part of the pen
`injector design and performance.
`
`m(4)
`
`Primary container closure system: The drug product is packaged in a 1.5-mL clear
`type I glass cartridge sealed with a
`(hm plunger on one end and a
`M 4) cap on the other end. Primary stability batches were stored in
`this primary container closure system. Packaging components meet requirements
`of USP<660> Glass and USP<381> and <87> Elastomeric Closures. The
`leachable
`(m4) has a limit ofM0 mcg/mL, which is found
`by the Pharmacology Toxicology team to be pose no safety risk. The same
`primary container closure system is approved for the liraglutide drug product (an
`approved product by the same applicant).
`Reference is made to the CDRH review of the pen injector, including any
`bridging information on different devices, if applicable.
`
`Expiration Date & Storage Conditions: The shelf life of the drug product is 36
`months at 5°C, and the in-use shelf life is 56 days at 5°C to 30°C after initial use.
`
`

`

`
`
`QUALITY REVIEW
`
`The long-term expiry is based on 18- to 36-month long-term data for six
`primary stability batches - scale), with three batches assembled in pen
`injectors. In addition, 3-month data are provided for three full-scale validation
`batches (-scale). The in-use expiry is based on 56-day data at 5°C and
`30°C for three primary stability batches. All batches were manufactured at the
`commercial site, using the commercial process with minor differences.
`
`C. Special Product Quality Labeling Recommendation: not applicable
`D. Life Cycle Knowledge Information] Final Risk Assessment:
`API
`none
`
`Drug product
`Process
`
`Facilities
`Microbiology
`
`none
`none
`
`page 10 of Chapter VI
`page 22 of Chapter VIII
`
`
`
`

`

`QUALITY ASSESSMENT
`
`NHCROBIOLOGY
`
`Product Background: —
`
`NDA: 209637
`
`Drug Product Name / Strength: OzempicO (semaglutide), 1.34 mglmL
`
`Route of Administration: subcutaneous injection
`
`Applicant Name: Novo Nordisk Inc.
`
`Manufacturing Site: Novo Nordisk AIS, Novo Allé 1, Bagsvzerd, Hovedstaden 2880,
`Denmark
`
`Method of Sterilization:
`
`(hm processing
`
`Review Recommendation: The submission is recommended for approval on the basis of
`sterility assurance.
`
`Review Summary:
`
`(m4)
`
`List Submissions being reviewed: 12/05/2016; 03/01/2017; 05/01/2017; 06/23/2017
`
`Highlight Key Outstanding Issues from Last Cycle: N/A
`
`Concise Description Outstanding Issues Remaining: None
`
`Supporting/Related Documents:
`0 DNIF #
`(W), Type V, for Novo Nordisk A/S, Novo Allé, 2880 Bagsvzerd, Denmark,
`for
`(m4) processing of the subject drug product.
`0 DNIF # WW review
`mm.doc, dated 07/24/2017, by E. Bearr. (Adequate)
`
`Remarks Section: Tables and container closure system figure are adapted from the submission.
`The most updated packaging instructions are provided in the applicant’s submission dated
`03/01/2017. The applicant’s submission dated 05/01/2017 is in response to the Agency’s
`
`

`

`QUALITY ASSESSM ENT
`
`Information Request dated 03/30/2017. The applicant’s submission dated 06/23/2017 is in
`response to the Agency’s Information Request dated 05/24/2017.
`
`S Drug Substance — Not applicable,
`
`M"
`
`R] Description of the Composition of the Drug Product
`0 Description of drug product — Clear, colorless, sterile solution, 1.34 mg/mL, pH
`
`(b) (4)
`
`, filled in a 1.5 mL cartridge and assembled in a PDSZ90 pen-injector for
`
`subcutaneous injection. The active drug substance is a peptide analogue for improvement
`
`of glycemic control.
`Dru
`-
`.roduct com n osition —
`
`USP/P11 Eur.
`mam— USP/JP/Ph Eur
`
`_
`
` Disodimn h Hhate deli drate
`
`~
`
`sto H74
`
`(5) (4)
`
`0 Description of container closure system — The primary packaging is a 1.5 mL cartridge
`with a plunger and.
`(but) rubber disc. The rubber disc is inserted into an aluminum cap
`
`(b) (4) I rubber plunger.
`
`The schematic of the closed cartridge provided below is adapted from Section 3.2.P.7,
`Cartridge 1.5 m1, System Report f0]
`(m4), p. 4.
`(mm
`
`The applicant states that there is no direct contact between the PDSZ90 pen-injector and
`
`the product. Two pen-injector variants are proposed:
`
`— PDSZ90 pen—injector for semaglutide 1.34 mg/mL (0.25 mg / 0.5 mg / 1.0 mg),
`which can deliver doses of 0.25 mg, 0.5 mg, or 1.0 mg.
`
`— PD8290 pen-injector for semaglutide 1.34 mg/mL (1.0 mg), which can only
`deliver doses of 1.0 mg.
`
`

`

`QUALITY ASSESSM ENT
`
`The submission indicates that the difference between the 2 pen-injector variants is limited
`to the imprint on the scale drum. The device is intended to function with a standard
`needle
`M“)
`
`Reviewer’s Assessment: The applicant provided an adequate description of the drug
`product composition and the container closure system designed to maintain product
`sterility.
`
`Acceptable
`
`P.2.5 Microbiological Attributes
`Container/Closure and Package Integrity
`(Section 2.3.P.2, Pharmaceutical Development; Section 3.2.P.2.57 Microbiological
`Attributes)
`
`The submission indicates that container closure integrity of the proposed cartridge sealed
`with the rubber disc is correlated with Residual Seal Force RSF).
`«0(4)
`
`The RSF test is performed by measuring the force as a fimction of movement of the
`testing-fixture.
`
`(m4)
`
`he correlation between RSF and CCI was determined by performing microbial
`ingress tests on cartridges filled with media and sealed with different RSF values. The
`cartridges were incubated according to the conditions used for media fill simulations (not
`provided) and then inspected for bacterial growth. The microbial ingress test is performed
`at time 0 and repeated at the end of shelf life. The lowest acceptable limit for the RSF
`value is determined based on the lowest RSF value tested where the filled cartridges
`show no sign of grth in the CCI test at the end of shelf life. The applicant indicates
`that CCIT is on-going to confirm the integrity at the end of shelf life and will be finalized
`in 2017. The RSF and microbial ingress test data are not provided. Additional
`information regarding CCIT was provided in DIVIF
`“(4)
`
`(too) was
`Note to Reviewer: The container-closure integrity validation provided in DMF #
`reviewed and found not adequate on 03/14/2017 in microbiology review D (”MMOSROI .doc,
`by E. Bearr.
`
`The following deficiency was issued by the Agency in the Information Request dated
`03/30/20 1 7.
`
`DMF #1
`
`00(4) has been reviewed andfound inadequate.
`
`In their response dated 05/01/2017, the applicant refers the Agency to the response
`submitted to DMF # N on 05/01/2017.
`
`12 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSM ENT
`
`Reviewer’s Assessment: The
`adequate. The
`
`one validation of the cartridges is
`M" validation of equipment and the
`validation of caps and plungers are also adequate.
`
`(I!) (4)
`
`Acceptable
`
`Media Fill Procedures and Specification and Actions Concerning Product When Media
`Fills Fail
`
`The subject NDA does not provide information concerning media fill procedures and
`specification and actions concerning product when media fills fail.
`
`Note to Reviewer: Media fill simulation validation and actions concerning product when media
`fills fail are provided in DMF #1
`(we). The 2015 — 2017 media fill simulations of the
`(m4)
`used for the 1.5 mL cartridge have been reviewed and found adequate in
`microbiology review D "'""M05Rordoo, dated 07/24/2017, by E. Bearr.
`
`Reviewer’s Assessment: The media fill simulation provided in DMF #
`one process for the subject drug product.
`
`(m4) validates the
`
`Acceptable
`
`P.5 Control of Drug Product
`
`P. 5.1 Specification
`
`The product release specification includes the following microbiological tests:
`
`
`
`
` USP <85>, kinetic chromogenic mediod
`USP <7l>, membrane filtration method
`
`
`
`Reviewer’s Assessment: The release specification contains adequate tests and acceptance
`criteria to ensure the microbiological quality of the subject drug product.
`
`Acceptable
`
`P.5.2 Analytical Procedures — see P.5.1 and P.5.3
`
`P.5.3 Validation of Analytical Procedures
`
`Endotoxins
`
`(Section 3.2.R, Bacterial Endotoxins Test, Suitability Test Report)
`
`The bacterial endotoxins level of the drug product is tested by USP <85>, kinetic
`chromogenic method. The endotoxins specification is i: IU/mL.
`(hm
`
`

`

`QUALITY ASSESSMENT
`
`Monograph limit. The lysate sensitivity is (no) IU/mL(
`. The drug potency is 1.34 mg/mL.
`
`W4)
`
`The submission indicates that for liquid samples, the concentration of sample solution
`equals 1 and is therefore omitted from the general formula for MVD (MVD = Endotoxin
`limit/X). Using the applicant’s general formula, the MVD =
`mm
`
`The test for interfering factors was performed in quadruplicate on batch #FW5L607,
`#FW5L608, and #FW5L609 using a test dilution of
`W"
`
`Acceptance criteria:
`
`(b) (4)
`
`0 The endotoxin % recovery for the positive product control must be between
`%.
`
`(D) (4)
`
`o The pH of the lysate / product mixture is within the range of
`
`Results: All acceptance criteria were met. The endotoxins % recovery ranged from (no)
`% for the three test batches. The pH was
`(“3 for each batch.
`
`Validation of the test shows no inhibition or enhancement using a dilution of
`dilution of
`mm will be used for routine testing.
`
`m“). A
`
`Finished lot # FW5M022, #FW5L981, and #FW5L887 contain m’EU/mL (Section
`3.2.P.5.4 Batch Analyses).
`
`1 mg
`Maximum dose for a 70 kg adult in 1 hour according to the package insert:
`Calculated endotoxin dose at the proposed endotoxins) specification and maximum dose:
`
`Reviewer’s Assessment: The bacterial endotoxins method is suitable for the drug product.
`The endotoxin dose at the proposed endotoxins specification and maximum dose as
`calculated by this reviewer is within the USP <85> recommendation of 8EUlkg/hr.
`
`Sterility
`
`Acceptable
`
`(m4)
`The sterility of the drug product is tested according to USP <71>,
`. The sterility test method validation was not provided. Finished lot # FW5M022,
`#FW5L981, and #FW5L887 met the release specification of sterility (complies) (Section
`3.2.P.5.4 Batch Analyses).
`
`The following deficiency was issued by the Agency in the Information Request dated
`03/30/20 1 7.
`
`

`

`QUALITY ASSESSMENT
`
`Please provide data supporting the suitability ofthe sterility test methodfor the subject
`drugproduct.
`
`. The suitability and routine test methods are the same.
`
`: LEIZ‘EUEULE‘V 7""
`
`In their response dated 05/01/2017, flle applicant provided the results of sterility test
`method suitability for the subject drug product. Suitability testing was erformed using 3
`batches of the dru
`roduct: FW5L887, FW5L981, and FW5M022.
`
`7”"
`
`

`

`Elizabeth
`Bearr
`
`Erika
`Pfeiler
`
`Digitally signed by Elizabeth Bearr
`Date: 7/25/2017 10:11:34AM
`GUID: 55370d1e00cfd67fc04d8bfbedbf3096
`
`Digitally signed by Erika Pfeiler
`Date: 7/25/2017 10:12:40AM
`GUID: 502d1da500002b6a73a00c0e0dff6e1d
`
`

`

` QUALITY REVIEW
`
`ATTACHNIENT I: Final Risk Assessments
`
`See Executive Summaly
`
`

`

`Su (Suong)
`Tran
`
`Digitally signed by Su (Suong) Tran
`Date: 7/27/2017 04:13:30PM
`GUID: 508da71f00029ec8b75e233f12b15339
`
`