CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`203441Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`Page 1
`
`NPS EX. 2063
`CFAD v. NPS
`IPR2015-01093
`
`

`
`MEMORANDUM
`
`Date: December 20, 2012
`
`To: NDA 203441
`
`From: Terrance Ocheltree, Ph.D., R.Ph.
`Director
`Division of New Drug Quality Assessment II
`ONDQA
`
`
`Subject: Tertiary review and Concurrence of ONDQA recommendation for NDA 203441,
`Gattex® teduglutide, for injection, 5 mg per vial (10 mg/mL after reconstituted). Teduglutide is a
`new molecular entity (NME).
`
`Teduglutide in NDA 203441 is proposed for the treatment of adult patients with short bowel
`syndrome (SBS) and improvement of intestinal absorption of fluid and nutrients.
`
` I
`
` have assessed the ONDQA reviews of NDA 203441 by Yichun Sun, Ph.D. and concur with the
`ONDQA recommendation of Approval. The initial ONDQA CMC review was entered into
`DARRTS on July 27, 2012, with a recommendation for a Complete Response due to an absence
`of a recommendation from the Office of Compliance on the manufacturing and testing sites,
`pending labeling issues and pending results for the methods validation consult. A methods
`validation consult was sent to the Division of Pharmaceutical Analysis (DPA), Office of Testing
`and Research. According to the Method Validation Report Summary entered into DARRTS by
`Michael Trehy, Ph.D. on November 21, 2012 the two HPLC methods were determined to be
`acceptable for quality control and regulatory purposes by Kallol Biswas, Ph.D. An ONDQA
`Biopharmaceutics review was not preformed due to the proposed dosage form. On December
`14, 2012 the Office of Compliance entered an Overall Recommendation of “Acceptable” into
`EES after the applicant withdrew the
` drug substance
`manufacturing site from the application. A second CMC review was entered into DARRTS on
`December 14, 2012 updating the status of the recommendation from the Office of Compliance,
`resolution of labeling issues and acceptability of the methods.
`
`Teduglutide for injection is supplied in a sterile, single-use 3-mL, USP Type I glass vial
`containing 5 mg of teduglutide as a white lyophilized powder in a 30-vial kit and a single-vial
`kit. The lyophilized powder is intended to be reconstituted with 0.5 mL of sterile Water for
`Injection (sWFI), USP, immediately before administration by subcutaneous injection. Each vial
`of teduglutide also contains 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium
`phosphate monohydrate, and 3.434 mg dibasic sodium phosphate heptahydrate. The sWFI is
`provided in a prefilled syringe. The product should be used within 3 hrs after reconstitution.
`
`
`The drug substance, teduglutide is manufactured by
`. A
` month retest date is recommended when the drug substance is stored
`at -20° ± 5°C or below.
`
`
`Reference ID: 3235434
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`Page 2
`
`

`
`The drug product, teduglutide for injection, is manufactured by Hospira, Inc, McPherson, KS.
`The Sterile Water for Injection (SWFI) prefilled syringes are manufactured by
`(mo
`
`The teduglutide and SWFI are co-packaged at
`
`Ma’
`
`A 36 months expiration dating period for the product stored refrigerated at 2°C to 8°C (36°F and
`46°F), prior to dispensing. Once dispensed to the patient the product may be stored at room
`temperature up to 25°C (77°F)
`ml’.
`
`The drug product is packaged in two configurations, a single—vial kit and a 30-vial kit. The
`single vial kit comes as one package (single box) with the non-drug components included in the
`box. The 30-vial kit comes as two packages, one for the drug product vials and another for the
`non-drug components. The box containing the non-drug components is stored at room
`temperature. The box containing the drug product vials must be stored refrigerated until
`dispensed. The packaging configuration then requires the dispensing pharmacist to remove the
`drug vials from their outer container, add the drug vials to the larger box containing the non-drug
`components, add a use by date to the outer carton and then dispense the whole kit which will be
`stored at room temperature by the patient
`('’m
`
`The kits are as described below:
`
`The product to be dispensed either a single-vial kit or a 30-vial kit. The single-vial kit is pre-
`assembled and ready to be used. It contains:
`One-vial kit (NDC 68875-0101-4):
`0 One single-use vial of drug
`
`0 One disposable prefilled syringe containing 0.5 mL Sterile Water for Injection USP for
`reconstitution, with a separate needle (22G x 11/2 in) to attach to the syringe
`0 One sterile disposable 1-mL syringe with needle (26G x 5/8 in) for dosing
`0 Four alcohol swabs
`
`The 30-vial kit is to be assembled by a pharmacist with the following two cartons:
`Carton of Drug (NDC 68875-0101-2):
`0 Thirty single-use vials of drug
`Carton of Ancillary Supplies (NDC 68875-0101-3):
`
`0
`
`disposable prefilled syringes containing 0.5 mL Sterile Water for Injection
`separate needles (22G x 11/2 in) to attach to the syringes for reconstitution
`
`0 Thirty sterile disposable l—mL syringes with needle (26G x 5/8 in)
`0 Sixty alcohol swabs
`
`Reconstitution of the lyophilized drug with 0.5 mL of preservative-free Sterile Water for
`Injection, provided in a prefilled syringe, is required prior to subcutaneous administration of the
`drug. Reconstituted GAITEX is a sterile, clear, colorless to light straw-colored 10 mg/mL
`solution, which is essentially fiee from particulates. Upon reconstitution with the 0.5 mL Sterile
`Water for Injection provided in the prefilled syringe, a maximum of 0.38 mL of the reconstituted
`solution which contains 3.8 mg of teduglutide can be withdrawn from the vial for dosing.
`
`Reference ID: 3235434
`
`Page 3
`
`Page 3
`
`

`
`The container carton labels for the two packaging configurations are not well designed.
`Valuable information is contained on the sides and bottom panels instead of the front (top) panel.
`Messages to the pharmacist related to storage and dispensing are not readily visible. Nor are
`instructions completely clear. For example, there is a place on the front label for the pharmacist
`to apply a
`(“(0. However, these issues do not
`affect the approval decision for this application.
`
`During the writing of this review it was also noted that the drug vials contained incorrect storage
`conditions.
`("M
`
`This was initially justified by stating that having multiple storage
`conditions on the label may confuse the patient and that the patient was the person most likely to
`see the individual vials (due to them being packaged in a kit). After a discussion with relevant
`members of the review team, it was determined that the vials should be labeled according to the
`requirements for long term stability. The Applicant was contacted on December 19, 2012 to
`inform them of this necessary change and also to request that the front panels contain a storage
`condition statement directed to the patient. The vial label was updated to state “Prior to
`dispensing, store at 2°C to 8°C (36°F to 46°F). Do not freeze” on December 20, 2012. The
`following statement will be added to the outer cartons front panel: "Attention patients: Store at
`room temperature up to 25°C (77°F). Do not freeze." Section 16 HOW SUPPLIED/STORAGE
`AND HANDLING of the package insert will be revised to be consistent with the outer cartons.
`
`I concur with the determination that the information as provided in the NDA is adequate to
`assure the identity, strength, purity, and quality of the drug product and support the
`recommended drug product shelf life as described above for the proposed commercial product
`when it is stored at controlled room temperature.
`
`There is one ONDQA related Post Marketing Commitment (PMC). The PMC calls for:
`“Elemental Impurities specifications will be expanded to include limits and testing for all metals,
`as recommended in USP <232>." This is to be implemented by the Applicant by March 31,
`2013.
`
`I concur with the determination that the information as provided in the NDA is adequate to
`assure the identity, strength, purity, and quality of the drug product and support the
`recommended drug product shelf life as described above for the proposed commercial product
`when it is stored at controlled room temperature.
`
`The secondary review of the CMC reviews was perfonned by Moo-Jhong Rhee, Ph.D.
`
`Reference ID: 3235434
`
`Page 4
`
`Page 4
`
`

`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TERRANCE W OCHELTREE
`12/20/2012
`
`Reference ID: 3235434
`
`Page 5
`
`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Memorandum
`
`
`
`
`
`
`
`
`
`
`
`Date: December 14, 2012
`
`From: Yichun Sun, Ph.D.
`
`Review Chemist, ONDQA
`
`Division of New Drug Quality Assessment II
`
`ONDQA
`
`Through: Moo-Jhong Rhee, Ph.D.
`Chief, Branch IV
`Division of New Drug Quality Assessment II
`ONDQA
`
`
`To: CMC Review #1 of NDA 203441
`
`Subject: Final Recommendation
`
`At the time when the CMC review #1 was written, there were three pending issues listed
`as follows:
`
`
`1) The overall acceptable recommendation of Establishment Evaluation was still
`pending.
`
`2) There were issues on the Label/Labeling that needed to be resolved.
`
`3) Report of Method Validation from the Division of Pharmaceutical Analysis,
`Office of Testing and Research, CDER was still pending.
`
`
`
`
`
`
`
` (Elemental Impurities) was raised by the review
`* Safety concern of
`team after the CMC review #1 was written.
`
`
`Establishment Evaluation
`After inspection, one of two the drug substance sites,
`is not acceptable due to GMP violations. A T-con was held with the NDA applicant on
`December 12, 2012 to discuss the options for the applicant to pursue. As there is another
`drug substance manufacture site
` for the
`NDA, the applicant decided to withdraw the unacceptable drug substance manufacture
`site during the T-con. An amendment to withdraw
` site was received on
`December 13, 2012.
`
`
`
`
`Reference ID: 3231508
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`Page 6
`
`

`
`On December 14, 2012, the Office of Compliance gave an overall “Acceptable”
`recommendation for all the facilities involved in the manufacture and test of the drug
`substance and drug product (Attachment - 1).
`
`Evaluation of Label/Labeling
`On November 9, 2012, the NDA applicant submitted an amendment providing the
`finalized mock up container and carton labels. Additionally, the applicant also agreed to
`all the CMC changes made to the package insert. All the labels/labeling issues are now
`satisfactorily resolved. The CMC sections of the final package insert, and mock up
`container and carton labels are attached (Attachment - 2).
`
`HPLC Method Validation
`On November 14, 2012, the report of method validation for the two HPLC methods used
`for quantitation of impurities in both drug substance and drug product in NDA 203441
`was received. The two HPLC methods were satisfactorily validated by Dr. Kallol
`Biswas from the Division of Pharmaceutical Analysis, Office of Testing and Research,
`CDER (Attachment - 3).
`
` Elemental Impurities
`The issue of safety concern of elemental impurities in the drug substance has been
`satisfactorily resolved (Attachment - 4).
`
`Recommendation:
`All the previous pending issues are now satisfactorily resolved, and therefore, from the
`ONDQA’s perspective, this NDA is recommended for APPROVAL.
`
` *
`
`
`
`
`
`Reference ID: 3231508
`
`2
`
`Page 7
`
`

`
`Attachment - 1 §Summa1_'x Regort of Establishment Evaluation)
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`NPS PHARMS INC
`550 HILLS DR 3RD FL
`BEDMINSTER_ NJ 07921
`Gaitex (teduglutide)
`
`Sponsor:
`
`Brand Name:
`Estab. Name:
`Generic Name:
`
`Product Numbov: Dosage Form: Ingredient: Strength:
`001: POWDER. FOR INJECTION SOLUTION. LYOPHILIZEDI
`TEDUGLUTIDE; IOMG
`
`NDA 203441/000
`180
`
`I 3
`
`0-NOV-Z011
`30-DEC-2012
`
`31 -OCT»2012
`
`c. TRAN-ZWANETZ
`Y. SUN
`M. KOWBLANSKY
`
`Project Manager
`Revsew chemist
`Team Leader
`
`(HI-‘D-800)
`
`3017963877
`3017961388
`3017961390
`
`Application:
`Org. Code:
`Priority:
`Stamp Date:
`PDUFA Date:
`Action Goal:
`District Goal:
`
`FDA Contacts:
`
`Overall Recommendation:
`
`ACCEPTABLE
`
`on 14-DEC-2012
`
`by D. SMITH
`
`(HFD—323)
`
`3017965321
`
`PENDING
`
`PENDING
`
`PENDING
`
`WITHHOLD
`
`PENDING
`
`WITHHOLD
`
`PENDING
`
`PENDING
`
`PENDING
`
`on 04-DEC-2012
`
`by EES_PROD
`
`on 20-SEP-2012
`
`by EES_PROD
`
`on O2-MAR-2012
`
`by EES_PROD
`
`on 02-MAR-2012
`
`Dy EES_PROD
`
`on O2~MAR-2012
`
`by EES_PROD
`
`on 25-JAN-2012
`
`by EES_PROD
`
`on 23-JAN-2012
`
`by EES_PROD
`
`on 23-JAN-2012
`
`by EES_PROD
`
`on 23-JAN-2012
`
`Dy EES_PROD
`
`Establishment:
`
`cm:
`
`:51:
`
`9”’
`
`151(4)
`
`DMF No:
`
`Responsibilities:
`
`Profile:
`
`Last Milestone:
`Milestone Date:
`
`Decision:
`
`Reason:
`
`DRUG SUBSTANCE MANUFACTURER
`
`OC RECOMMENDATION
`2o..IUL.2o12
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`AADA:
`
`(|I)(4)
`
`OAI Status:
`
`NONE
`
`December 14. 2012 10:07 AM
`
`FDA Confidential - Internal Distribution Only
`
`Page 1 of 5
`
`Reference ID: 3231 508
`
`Page 8
`
`Page 8
`
`

`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Eehbllehment:
`
`CFN:
`
`1925262
`
`FEI:
`
`‘lQ5282
`
`HOSPIRA WORLDWDE. INC
`
`DIE No:
`
`MCPHERSON. . UNITED STATES 674609301
`
`AADA:
`
`Responsiblities:
`
`FIMSHED DOSAGE MANUFACTURER
`
`ON Status:
`
`NONE
`
`AADA:
`
`OAI Status:
`
`NONE
`
`AADA:
`
`OAI Status:
`
`NONE
`
`Profile:
`
`Lag; mggggme;
`
`Milestone Date:
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`23-MAR-2012
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Eshbllshment:
`
`CFII:
`
`El:
`
`
`
`21-MAY-2012
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`CFII:
`
`El:
`
`OC RECOMMENDATION
`
`30-JAN-2012
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`DIE No:
`
`Responslblltles:
`
`Profile:
`
`Mllestone Date:
`
`Declslm:
`
`Reason:
`
`Establishment:
`
`Dlf No:
`
`Responelbiitles:
`
`Profile:
`
`Lug flflgsmngg
`
`Milestone Date:
`
`Declslon:
`
`Reason:
`
`December 14. 2012 10:01 AM
`
`FDA Confidential - Internal Disttibution Only
`
`Page 2 of 5
`
`Reference ID: 3231508
`
`Page 9
`
`Page 9
`
`

`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`cm:
`
`FEI: -
`
`AADA:
`
`OAI status:
`
`NONE
`
`OC RECOMMENDATION
`
`24-SEP-2012
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Prom-= _ on-am-u=
`
`~o~e
`
`
`
`24-SEP-2012
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`CFN:
`
`OC RECOMMENDATION
`04-DEC-2012
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`AADA:
`
`OAI status:
`
`NONE
`
`DH-' No:
`
`Responsibilities:
`
`Profile:
`
`Lug m|.,¢.n.;
`
`Mnestone Date:
`
`Decision:
`
`Reason:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`Establishment:
`
`DIE No:
`
`Responsibllltles:
`
`Profile:
`
`L”: ""310",;
`Milestone Date:
`
`Decision:
`
`Reason:
`
`December 14. 2012 10:07 All
`
`FDA confidential - Imemal Dlsttlbuilon Only
`
`Page 3 oi 6
`
`Refelenoe ID: 3231508
`
`Page 10
`
`Page 10
`
`

`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Eshhllchment:
`
`CFN:
`
`FE: -
`
`
`
`OC RECOMMENDAHON
`
`24-JAN-201 2
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`December 14. 2012 10:07 AM
`
`FDA conildential - Internal Dlstrihutlon Only
`
`Page 4 of 5
`
`Reference ID: 3231508
`
`Page 1 1
`
`DIE No:
`
`Responslblities:
`
`Proflie:
`
`Lg“ Mflggtongg
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`Establishment:
`
`DIF No:
`
`Responslbllties:
`Profile:
`
`L.“ 33,530.“;
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`Establishment:
`
`DRF No:
`
`Responsibllues:
`
`Profile:
`
`Last Mlestone:
`
`Milestone Date:
`
`Decision:
`
`R0180":
`
`DC RECOMMENDATION
`
`07-FEB-2012
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`CFN:
`
`FE:
`
`OC RECOMMENDATION
`
`24-JAN-2012
`
`ACCEPTABLE
`
`BASED ON FILE REVIEW
`
`CFN:
`
`AADA:
`
`OAI status:
`
`NGJE
`
`AADA:
`
`OAI Statue:
`
`NONE
`
`AADA:
`
`OAI status:
`
`NGIE
`
`Page 11
`
`

`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`cm: 2 sen: _
`
`
`
`AADA:
`
`OAI status:
`
`NONE
`
`OC RECOMMENDATION
`04050-2012
`
`ACCEPTABLE
`
`DISTRICT REc0MMENDA11ON
`
`Eshhllshmont:
`
`DIS No:
`
`Responsibilities:
`
`Profile:
`
`L.“ flflggfgngg
`Milestone Date:
`
`o¢¢|;|on:
`
`Reason:
`
`
`Establishment:
`
`CHI:
`
` DIE No:
`
`Raponslhllmos:
`
`Profile:
`
`AADA:
`
`OAI sum:
`
`NONE
`
`L.“ Mflggfong;
`Mllestone Date:
`
`Declsionz
`
`Re-son:
`
`OC RECOMMENDATION
`04-DEC-2012
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`December 14. 2012 10:07 AM
`
`FDA Confidential - Internal Distributlon Only
`
`Page 5 of S
`
`Reference ID: 3231508
`
`Page 12
`
`Page 12
`
`

`
`Attachment - 2 CMC Sections of the Finalized Labelin and Labels
`
`Reference ID: 3231508
`
`Page 13
`
`

`
`Attachment - 3 (1\_/Iethod Validation)
`
`According to the method validation report provided by Dr. Kallol Biswas from the
`Division of Pharmaceutical Anal sis, Office of Testin and Research, CDER, the I-IPLC
`
`
`
`
`Therefore, it is concluded that the two I-IPLC methods used
`
`or quantrtatron o impurities in both drug substance and drug product in NDA 203441
`are satisfactorily validated and acceptable to be used to ensure the purity of the drug
`substance and drug product in the NDA.
`
`Attachment - 4 [Elemental Impurities}
`
`Safety concern0- was raised by the review team. Detailed information
`regarding this issue and its resolution are summarized as follows:
`
`An IR letter dated May 15, 2012 was sent to re uest the NDA applicant to add a test
`method and an acceptance criterion for
`to the drug substance
`specification. In the responding amendment dated June 18, 2012, the applicant
`Pharmaceuticals) agreed to add a test method and acceptance criterion for
`to the drug substance specification. However, the applicant proposed to implement this
`change as a post approval commitment. FDA had accepted the proposal as a post
`approval commitment in June 2012.
`
`S
`
`
`
`Reference ID: 3231508
`
`22
`
`Page 14
`
`Page 14
`
`

`
`
`
`Reference ID: 3231508
`
`23
`
`(b) (4)
`
`Page 15
`
`

`
`
`
`
`
`Reference ID: 3231508
`
`24
`
`(b) (4)
`
`Page 16
`
`

`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`YICHUN SUN
`12/14/2012
`
`MOO JHONG RHEE
`12/14/2012
`Chief, Branch IV
`
`Reference ID: 3231508
`
`Page 17
`
`

`
`
`
`NDA 203-441
`
`Gattex® (teduglutide [rDNA origin]) for injection
`
`NPS Pharmaceuticals
`
`Yichun Sun, Ph.D.
`
`Branch IV
`
`Division of New Drug Quality Assessment II
`
`Office of New Drug Quality Assessment
`
`CMC REVIEW OF NDA 203-441
`
`For the Division of Gastroenterology and Inborn Errors Products
`(HFD-180)
`
`Reference ID: 3166028
`
`1/271
`
`Page 18
`
`Page 18
`
`

`
`
`
`Table of Contents
`
`Table of Contents ..................................................................................................................................................... .. 2
`
`Chemistry Review Data Sheet ................................................................................................................................. ..4
`
`The Executive Summary .......................................................................................................................................... .. 8
`
`1. Recommendations ................................................................................................................................................ .. 8
`
`A. Recommendation and Conclusion on Approvability .................................................................................. .. 8
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments. Agreements, and/or Risk Management
`Steps, if Approvable .................................................................................................................................... .. 8
`
`II. Summary of Chemistry Assessments ................................................................................................................. .. 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ........................................................................ .. 8
`
`B. Description of How the Drug Product is Intended to be Used ................................................................... .. 10
`
`Gattex (teduglutide [IDNA origin]) for injection is a glucagon-like peptide-2 (GLP-2) analog indicated for: 10
`
`E1 The treatment of adult patients with short bowel syndrome (SBS). ......................................................... ..10
`
`D Improvement of intestinal absorption of fluid and nutrients. .................................................................... .. 10
`
`The recommended dose of Gattex is 0.05 mg/kg given subcutaneously once daily. It can not be used for
`intravenous or intramuscular injection. It is a single-use vial. The product should be used within 3 hrs
`after reconstitution. ................................................................................................................................... .. 10
`
`C. Basis for Not-Approval Recommendation ................................................................................................. .. 10
`
`1]]. Administrative ................................................................................................................................................. ..11
`
`A. Reviewer’s Signature ................................................................................................................................. ..11
`
`B. Endorsement Block .................................................................................................................................... .. 11
`
`Chemistry Assessment ........................................................................................................................................... .. 12
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ............................... .. 12
`
`s DRUG SUBSTANCE [Teduglutide,
`
`""“’] ........................................................................... .. 12
`
`"”“’] ..................................................................... ..12
`S.l General Information [Teduglutide
`This section is satisfactory. ....................................................................................................................... ..12
`S.2 Manufacture [Teduglutide.
`°”“’] ................................................................................. ..13
`S.2.1 Manufacturers ................................................................................................................................. .. 13
`S.3 Characterization [Teduglutide,
`""("] ........................................................................... ..51
`S.4 Control of Drug Substance [Teduglutide,
`Mm] .......................................................... ..66
`S.5 Reference Standards or Materials [Teduglutide,
`"”‘°] .............................................. ..108
`S.6 Container Closure System [Teduglutide.
`"”“’] ......................................................... .. 119
`s.7 Stability [Teduglutide,
`""“’] ...................................................................................... ..12o
`P DRUG PRODUCT [Gattex (teduglutide[rDNA o1ign]) for injection] ...................................................... ..134
`
`Reference ID: 31 66028
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`CHEMISTRY REVIEW
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`""""\
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`P.1 Description and Composition of the Drug Product [Gattex (teduglutide [rDNA on'gn]) for injection]
`................................................................................................................................................................. .. 134
`
`P.2 Pharmaceutical Development [Gattex (teduglutide [rDNA orign]) for injection] .......................... ..135
`P.3 Manufacture [Gattex (teduglutide [rDNA orign]) for injection] ...................................................... ..163
`P.4 Control of Excipients [Gattex (teduglutide [rDNA orign]) for injection] ........................................ ..186
`P.5 Control of Drug Product [Gattex (teduglutide [rDNA on'gn]) for injection] ................................... ..187
`P.6 Reference Standards or Materials [Gattex (teduglutide [rDNA orign]) for injection] ..................... .. 209
`P.7 Container Closure System [Gattex (teduglutide [rDNA orign]) for injection] ................................ .. 210
`P.8 Stability [Gattex (teduglutide [rDNA orign]) for injection] ............................................................ .. 214
`A APPENDICES ...................................................................................................................................... ..234
`
`R REGIONAL INFORMATION ................................................................................................................. ..236
`
`H. Review Of Common Technical Doclnnent-Quality (Ctd-Q) Module 1 ......................................................... .. 236
`
`A. Labeling & Package Insert ...................................................................................................................... .. 236
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion............................................................. .. 263
`
`III. List Of Deficiencies To Be Resolved ............................................................................................................ .. 265
`
`IV. Attachment: .................................................................................................................................................... .. 266
`
`Reference ID: 3166028
`
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`
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`Chemistry Assessment Section
`
`Chemistry Review Data Sheet
`
`. NDA2 203-441
`
`_ REVIEW #: 1
`
`. REVIEW DATE: 27-July-2012
`
`. REVIEWER2 Yichun Sun, Ph.D.
`
`_ PREVIOUS DOCUMENTS:
`
`Previous Docmnents
`
`Document Date
`
`IND 58,213
`
`27-April-1999
`
`17-November-2003
`
`EOP 2 meeting Memorandum (IND 58,213)
`
`. SUBMISSION(S) BEING REVIEWED:
`
`Submission Reviewed
`@ 30-November-2011
`18-June-2012
`29-June-2012
`
`10-1111 -2012
`
`_ NAME & ADDRESS OF APPLICANT:
`
`Name: NPS Pharmaceuticals
`
`Address:
`
`550 Hills Drive, 3rd Floor
`
`Bedminster, NJ 07921
`
`Representative: Sandra C. Cottrell, MA, Ph.D.
`
`Telephone: 908-450-5300
`
`_ DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietaly Name: Gattex
`b) Non-Proprietary Name (USAN): Teduglutide
`c) Code Name/# (ONDQA only): N/A
`d) Chem. TypelSubmission Priority (ONDQA only):
`
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`Chemistry Assessment Section
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`0 Chem. Type: 1
`
`0 Submission Priority: Standard Review
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b)(l)
`
`10. PHARMACOL. CATEGORY: Analogue of the human glucagon-like peptide-2
`
`11. DOSAGE FORM: For injection
`
`12. STRENGTH/POTENCY: 5 mg per vial (10 mg/mL after reconstituted)
`
`13. ROUTE OF ADMINISTRATION: Subcutaneous injection
`
`14. Rx/OTC DISPENSED:
`
`_)_(_Rx
`
`OTC
`
`15. SPOTS SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM :
`
`X
`
`SPOTS product — Form Completed
`
`Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Teduglutide
`
`
`
`Primary Sequence of Teduglutide
`
`Empirical formula: C154H252N44O55S
`Molecular weight: 3752 Daltons
`
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`17. RELATEDISUPPORTING DOCUMENTS:
`
`A. DMFs:
`
` @ STATUS WW
`
`ITEM
`
`2 DATEREVIEW
`
`mm
`
`
`
`-K1
`II
`H-
`
`
`
`
`j
`-fl
`
`
`
`
`W"
`
`I
`
`
`
`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 — Suflicient 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)
`
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`Chemistry Assessment Section
`
`B. Other Documents: NA
`
`18. STATUS:
`
`ONDQA:
`CONSULTSI CMC
`
`REVIEWS
`N/A—1‘
`In
`In
`In
`“I
`Methods ValidationIt
`DMEPA n_
`EA
`Claim for Categorical
`See p.263
`Y. Sun
`Exclusion is granted.
`
`
`
`0 li Microbiolo
`
`March 30,2012
`
`B anS.Rile ,Ph.D.
`
`Note: The request of methods validation consult was sent to the Division of Pharmaceutical
`Analysis (DPA), Office of Testing and Research on February 23, 2012. The results of method
`validation from DPA are pending. The NDA is recommended for approval without completion of
`the validation of the methods.
`
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`
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`Chemistry Assessment Section
`
`The Chemistry Review for NDA 203-441
`
`The Executive Summagz
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`This NDA has provided sufficient information to assure identity, strength, purity, and
`quality of the drug product.
`
`However, the Office of Compliance has not made an overall ‘acceptable’ recommendation
`for the facilities involved in this application as of this review date.
`
`The label/labeling issues have not been resolved yet.
`
`Therefore, from the ONDQA perspective, this NDA is not recommended for approval in
`its present form per 21 CFR 314.125 (b)(6),(13) until all those remaining issues are
`satisfactorily resolved.
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or
`
`Risk Management Steps, if Approvable
`The applicant was requested to add a test method and an acceptance criterion for M")
`to the drug substance specification in the IR letter dated May 15, 2012.
`
`"M to the
`The applicant agreed to add a test method and acceptance criterion for
`drug substance specification in the amendment dated June 18, 2012. The applicant is
`currently developing a suitable procedure for teduglutide drug substance and plans to test
`representative batches, establish acceptance criteria, and will subsequently add this test to
`the drug substance specification. The applicant proposes to implement this as a post
`approval commitment.
`
`H. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Substance
`
`The active ingredient used in Gattex (teduglutide [IDNA origin]) for injection, which is
`indicated for the treatment of adult patients with short bowel syndrome (SBS) and for
`improving intestinal absorption of fluid and nutrients, is teduglutide (IDNA origin).
`Teduglutide (rDNA origin) is a 33 amino acid glucagon-like peptide-2 (GLP-2) analog
`manufactured using a strain ofEscherichia coli (E. coli) modified by recombinant DNA
`technology.
`W0
`The manufactlning process of teduglutide includes the following steps:
`
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`Chemistry Assessment Section
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`Teduglutide drug substance is a clear, colorless to li
`tedu utide in
`ueous buffer.
`
`t straw colored li uid co
`
`Drug Product
`
`The drug product, Gattex (teduglutide [rDNA origin]) for injection, is proposed to be used
`to treat short bowel syndrome (SBS) and, to improve intestinal absorption of fluid and
`nutrients. Teduglutide for injection is supplied in a sterile, single-use 3-mL, USP Type I
`glass vial containing 5 mg of teduglutide as a white lyophilized powder. Each vial also
`contains 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium phosphate
`monohydrate, and 3.434 mg dibasic sodium phosphate heptahydrate. The lyophilized
`powder is intended to be reconstituted with 0.5 mL of sterile Water for Injection (sWFI),
`USP, which is provided in a prefilled syringe, immediately before administration by
`subcutaneous injection. The reconstituted drug product is a nominal 10 mg/mL, sterile,
`clear, colorless to light straw-colored solution. The reconstituted solution has a pH of
`approximately 7.4. Up to 0.38 mL of the reconstituted solution can be withdrawn using a
`co-packaged dosing syringe for subcutaneous injection. The drug product is manufactured
`using an aseptic process. The manufacture of teduglutide for injection is comprised of the
`following steps:
`
`
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`Chemistry Assessment Section
`
`(5) (4)
`
`The identity, strength, purity and quality of the drug
`product are adequately controlled by the drug product specification. The proposed
`expiration dating period of 36 months is supported by the long-term stability data
`provided. The proposed storage time period and condition
`for the drug product by patients is also supported by the stability data. The results of in-
`use stability study of the reconstituted drug product demonstrated that the reconstituted
`drug product is stable for up to 24 hours at room temperature. The drug product would
`qualify for categorical exclusion from the preparation of an environmental assessment
`according to 21 CFR 25.31(b).
`
`(II) (4)
`
`B. Description of How the Drug Product is Intended to be Used
`
`Gattex (teduglutide [IDNA origin]) for injection is a glucagon-like peptide-2 (GLP