`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203565Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Application:
`
`Org. Code:
`
`Priority:
`
`NDA 203565/000
`
`Sponsor:
`
`LUITPOLD PHARMS
`
`161
`
`5
`
`800 ADAMS AVE STE 100
`
`NORRISTOWN, PA 19403
`
`Stamp Date:
`
`03-OCT-2011
`
`Brand Name:
`
`Injectafer
`
`PDUFA Date:
`
`Action Goal:
`
`District Goal:
`
`30-JUL-2013
`
`31-MAY-2013
`
`FDA Contacts: S. LIN
`
`S. LANGILLE
`
`J. MARTIN
`
`A. BAIRD
`
`J. BROWN
`
`Estab. Name:
`
`Ferric Carboxymaltose
`
`Generic Name:
`
`Product Number; Dosage Form; Ingredient; Strengths
`
`001; INJECTION; FERRIC CARBOXYMALTOSE; 50MG
`
`Prod Qual Reviewer
`
`Micro Reviewer
`
`Product Quality PM
`
`Regulatory Project Mgr
`
`Team Leader
`
`(HFD-805)
`
`(HFV-530)
`
`3017961403
`
`3017961557
`
`3017962072
`
`3017964969
`
`3017961652
`
`Overall Recommendation:
`
`ACCEPTABLE
`
`PENDING
`
`ACCEPTABLE
`
`PENDING
`
`WITHHOLD
`
`on
`
`on
`
`on
`
`on
`
`on
`
`by J. WILLIAMS
`
`by EES_PROD
`
`by J. WILLIAMS
`
`by EES_PROD
`
`()
`
`()
`
`3017964196
`
`3017964196
`
`by D. SMITH
`
`(HFD-620)
`
`2402769592
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE OTHER TESTER
`
`FINISHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`05-JUL-2013
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`July 22, 2013 2:28 PM
`
`FDA Confidential - Internal Distribution Only
`
`Page 1 of 5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`16-APR-2013
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`02-MAY-2013
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`20-MAR-2013
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`July 22, 2013 2:28 PM
`
`FDA Confidential - Internal Distribution Only
`
`Page 2 of 5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`17-APR-2013
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE MANUFACTURER
`
`FINISHED DOSAGE PACKAGER
`
`Profile:
`
`
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`OC RECOMMENDATION
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`26-APR-2013
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`04-FEB-2013
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`July 22, 2013 2:28 PM
`
`FDA Confidential - Internal Distribution Only
`
`Page 3 of 5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`27-JUN-2013
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`16-APR-2013
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Establishment:
`
`CFN:
`
`FEI:
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE OTHER TESTER
`
`Profile:
`
`CONTROL TESTING LABORATORY
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`16-APR-2013
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`July 22, 2013 2:28 PM
`
`FDA Confidential - Internal Distribution Only
`
`Page 4 of 5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Establishment:
`
`CFN:
`
`9613378
`
`FEI:
`
`3002808450
`
`VIFOR INTERNATIONAL INC.
`RESCHENSTRASSE 37
`
`DMF No:
`
`ST. GALLEN, , SWITZERLAND CH-9001
`16967
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE MANUFACTURER
`
`Profile:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`Reason:
`
`OC RECOMMENDATION
`
`04-FEB-2013
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`July 22, 2013 2:28 PM
`
`FDA Confidential - Internal Distribution Only
`
`Page 5 of 5
`
`

`

`
`
`MEMORANDUM
`
`July 8, 2013
`William M. Adams, CMC Reviewer
`NDA 203565
`Final OC recommendation for NDA 203565 in EES
`
`
`
`DATE
`FROM
`TO
`SUBJECT
`
`NDA 203565 for Injectafer® (ferric carboxymaltose injection) re-submitted on 30 Jan
`2013 with manufacture and control sites that differ from those listed in the initial NDA
`submission. CMC Review #3 (dated 25-Jun-2013) concluded that the application should
`not be approved in that an overall acceptable recommendation from the Office of
`Compliance and labeling issues were pending.
`
`The Office of Compliance issued an overall recommendation of Acceptable on 05-Jul-
`2013 and labeling meetings have been scheduled. Accordingly, from a CMC perspective,
`NDA 203565 is considered to be acceptable for approval.
`
`
`
`
`
`
`
`
`
`
`cc:
`DHP/RPM/A.Baird
`DNDQA I/PMQ/J.Martin
`DNDQA I/CMC Lead/J.Brown
`
`
`__________________
`William M. Adams
`CMC Reviewer, Branch II/DNDQA I/ONDQA
`
`__________________
`Ali al Hakim, Ph.D.
`Chief, Branch II/DNDQA I/ONDQA
`
`Reference ID: 3343917
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM M ADAMS
`07/19/2013
`
`ALI H AL HAKIM
`07/21/2013
`
`Reference ID: 3343917
`
`

`

`FEED
`
`rmn
`A
`
`NDA 203,565
`
`Injectafer® (Ferric Carboxymaltose Injection)
`50 mg Iron/mL
`
`Luitpold Pharmaceuticals, Inc.
`
`William M. Adams
`
`Division of New Drug Quality Assessment I/Branch II
`Office of New Drug Quality Assessment
`
`For the Division of Hematology Products
`Office of Hematology and Oncology Products
`
`Reference ID: 3332239
`
`

`

`Table of Contents .....................................................................................................2
`
`CMC Review Data Sheet .........................................................................................4
`
`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 CMC 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
`
`CMC Assessment.................................................................................................... 10
`
`I. Review Of Common Technical Document-Quality (Ctd—Q) Module 3.2: Body Of Data 10
`
`S DRUG SUBSTANCE ................................................................................................................... 10
`8.1
`General Information ..................................................................................................................... 10
`8.2
`Manufacture .................................................................................................................................. 10
`S3
`Characterization............................................................................................................................ 10
`
`SA
`5.5
`
`8.6
`8.7
`
`Control of Drug Substance ........................................................................................................... 10
`Reference Standards or Materials ...............................................................................................21
`
`Container Closure System ............................................................................................................22
`Stability ..........................................................................................................................................22
`
`P DRUG PRODUCT ....................................................................................................................... 22
`
`P.1
`P.2
`R3
`
`PA
`P.5
`R6
`
`R7
`P.8
`
`Description and Composition of the Drug Product....................................................................22
`Pharmaceutical Development ......................................................................................................22
`Manufacture ..................................................................................................................................23
`
`Control of Excipients ....................................................................................................................31
`Control of Drug Product ..............................................................................................................31
`Reference Standards or Materials ...............................................................................................39
`
`Container Closure System ............................................................................................................39
`Stability ..........................................................................................................................................41
`
`A APPENDICES ............................................................................................................................. 42
`
`A.1
`A.2
`A3
`
`Facilities and Equipment (biotech only)......................................................................................42
`Adventitious Agents Safety Evaluation .......................................................................................42
`Novel Excipients ............................................................................................................................42
`
`R REGIONAL INFORMATION .................................................................................................. 42
`
`CMC Review 03
`
`Reference ID: 3332239
`
`Page 2 of 45
`
`

`

`rnen
`
`Fnth‘
`
`R1 Executed Batch Records....................................................................................................................42
`
`R2 Comparability Protocols ...................................................................................................................43
`R3 Methods Validation Package ............................................................................................................43
`
`II. Review Of Common Technical Document-Quality (Ctd—Q) Module 1 .............................43
`
`A. Labeling & Package Insert.......................................................................................................... 43
`
`B. Environmental Assessment 01' Claim 01' Categorical Exclusion ............................................ 45
`
`III. List Of Deficiencies to be Communicated............................................................................45
`
`CMC Review 03
`
`Reference ID: 3332239
`
`Page 3 of 45
`
`

`

`
`
`CMC Review Data Sheet
`
`CMC Review Data Sheet
`
`1.
`
`NDA 203,565
`
`2.
`
`3.
`
`4.
`
`5.
`
`REVIEW 03
`
`REVIEW DATE: 25 Jun 2013
`
`REVIEWER: William Adams
`
`PREVIOUS DOCUMENTS:
`
`__ 8
`
`
`
`
`09 Jul 2012
`— CMC Review 02 EES conclusion
`—_ 23 Jul 2012
`
`6.
`
`SUBNIISSION(S) BEING REVIEWED:
`
`m_r-::—-:—
`
`mum——
`_—
`
`7.
`
`NANIE & ADDRESS OF APPLICANT:
`
`Name:
`
`_
`Address'
`
`Luitpold Pharmaceuticals. Inc.
`PO Box 9001. One Luitpold Drive
`Shirley. NY 11967
`
`CMC Review 03
`
`Reference ID: 3332239
`
`Page 4 of 45
`
`-008
`
`8-0 12
`S-013
`
`Response to 03/26/12 CMC IR letter
`Response to FDA request
`Response to FDA request for NDA section 3.2.S.4.4
`Up-dated in-use stability data
`Revised heavy metal limits
`Response to 05/30/12 CMC IR letter
`CMC Review 01
`
`13 Apr 2012
`23 Apr 2012
`24 Apr 2012
`27 Apr 2012
`16 May 2012
`06/ J11 2012
`08 Jim 2012
`
`

`

`
`
`CMC Review Data Sheet
`
`Marsha E. Simon
`
`Representative:
`
`800 Adams Avenue. Suite 100
`Norristown. PA 19403
`
`Telephone:
`
`610-650-4200
`
`8.
`
`DRUG PRODUCT NAME/CODE/I'YPE:
`
`Injectafer®
`a) Proprietary Name:
`Ferric Carboxymaltose Injection
`b) Non-Proprietary Name (USAN):
`VIT-45
`c) Code Name/# (ONDQA only):
`d) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chemical Type:
`
`2
`
`0 Submission Priority:
`
`Standard
`
`9.
`
`LEGAL BASIS FOR SUBMISSION: 505(b)(l)
`
`l0.
`
`PHARMACOL. CATEGORY: Treatment of iron deficiency anemia
`
`11.
`
`DOSAGE FORM: Injection for IV infusion
`
`12.
`
`STRENGTH/POTENCY: 50 mg iron/mL
`
`13.
`
`ROUTE OF ADMINISTRATION: IV infusion
`
`14.
`
`Rx/OTC DISPENSED:
`
`‘1 Rx
`
`OTC
`
`15.
`
`SPOTS {SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM}:
`
`SPOTS product — Form Completed
`
`
`‘1 Not a SPOTS product
`
`16.
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`Molecular Formula
`Molecular Weight
`Molecular Structure
`
`[Fe0,(OH)y(H20)z],,{(C5H1005)m(C5H1207)1]k where n=~1000. m=~8. l=~l 1. k=~4
`~ 1 50.000 daltons
`see CMC Review 01
`
`17.
`
`RELATED/SUPPORTING DOCUMENTS:
`
`A.
`
`Supporting DMFs:
`
`mn— Item Referenced -m——
`Vifor
`drug substance (VIT-45
`4
`active
`International
`- owder)
`
`—— "’""
`
`CMC Review 03
`
`Reference ID: 3332239
`
`Page 5 of 45
`
`

`

`04/15/11
`
`1 Action codes for DMF Table:
`l — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6— DMF not available
`
`7— Othe1 (explain under "Comments")
`2Adequate, Inadequate, or N/A (The1e'1s enough data'1n the application, the1efo1e the DMF
`did not need to be leviewed)
`3 Include reference to location in most recent CMC review
`
`B.
`
`Other Supporting Documents:
`
`
`
`Item Referenced mum-_—
`VIT-45 Injection/ Active as of
`Injectafer®
`05/06/06
`
`Injectafer®
`
`Not approved as
`of 03/1 1/08
`
`IND 63.243
`
`NDA 22.054
`
`Luitpold
`Pharmaceuticals
`orristown. PA
`
`Luitpold
`Phannaceuticals
`orristown. PA
`
`18.
`
`CONSULTS/CMC-RELATED REVIEWS:
`
`—m——“
`
`Date
`
`Pendin 0C overall conclusion
`04/17/12
`— GMP for CMC sites
`_M—
`DMEPA
`02/23/12
`ace ted
`
`_—__ mam MD“
`
`22054 thus not for this NDA
`
`__———
`
`Validation
`
`—_———
`
`CMC Review 03
`
`Reference ID: 3332239
`
`Page 6 of 45
`
`

`

`
`
`Executive Summary Section
`
`The CMC Review for NBA 203,565
`
`The Executive Summagy
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`Complete and acceptable chemistry, manufacturing, and controls (CMC) information has been
`provided to support approval of this application, however an overall recommendation by the
`Office of Compliance (0C) for the GIVIP inspections of the proposed manufacturing and testing
`facilities for the drug substance and drug product is still pending. Therefore, the application
`cannot be approved.
`
`Based on the provided stability data, a 24-month expiration dating period is granted for the drug
`product when stored at the USP controlled room temperature.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None
`
`H.
`
`Summary of CMC Assessments
`
`A.
`
`Description of the Drug Product(s) and Drug Substance(s)
`
`DRUG SUBSTANCE
`
`Ferric carboxymaltose is a complex of polynuclear iron(III)—hydroxide with 4(R)—(poly—(1—»4)—
`0-a-D—glucopyranosyl)-oxy-2R,3S,5R,6—tetrahydroxy—hexanoate with a relative molecular
`weight of approximately 150,000 daltons. Bulk drug is a brown amorphous powder readily
`soluble in water, but insoluble in most organic solvents (e.g.,
`M”).
`
`Complete and acceptable CMC information is provided in type II drug master file (DMF) 16967,
`owned by Vifor International, Inc., and summarized in the application. A letter of authorization
`for the DIVIF has been provided. DMF 16967 was reviewed on 07—Jun-2012 and found to be
`adequate to support this application. No significant changes have been made to the DIVIF since
`that review. Vifor is responsible for drug substance manufacture and all testing except residual
`solvents testing which is performed by a contract laboratory.
`
`The proposed drug substance is a new complex of iron rather than a new molecular entity
`(NME). Although ferric carboxymaltose has not been approved for use in a commercial drug
`product, the active moiety is iron (III). In addition, there are multiple FDA approved iron (III)-
`
`CMC Review 03
`
`Reference ID: 3332239
`
`Page 7 of 45
`
`

`

`
`
`Executive Summary Section
`
`carbohydrate drug products for which iron (11]) is the active moiety and drug product strength is
`expressed in terms of iron content (e.g., iron dextran injection and iron sucrose injection).
`
`All CMC issues regarding drug substance were resolved in the first review cycle. The
`resubmission proposes no changes to the drug substance section of the NDA. The CMC
`information regarding drug substance is acceptable to support approval of the application,
`however an overall conclusion by CC for the application is still pending.
`
`DRUG PRODUCT
`
`Injectafer® (fenic carboxymaltose injection) is a dark brown, sterile, aqueous solution intended
`for intravenous use in the treatment of iron deficiency anemia in patients intolerant to oral iron
`preparations or with chronic kidney disease. The drug product is designed to release usable iron
`(H1) to the iron transport and storage proteins in the body.
`
`Injectafer® will be marketed as a 15 mL single-use glass vial containing 750 mg of iron,
`formulated as ferric carboxymaltose, at 50 mg iron/mL strength. Drug product contains ferric
`carboxymaltose in water for injection with no excipients except sodium hydroxide and/or
`hydrochloric acid which are added to adjust the pH.
`
`sterilization. The
`processing followed by
`The drug product is manufactured by
`manufacturing process and controls are described in sufficient detail. No quality by design
`information is provided and design spaces are not proposed. The process has been reviewed and
`found acceptable for sterility assurance at the proposed drug product manufacturing site.
`
`(5) (4)
`
`(51(4)
`
`The specification for product release and stability testing is acceptable in that the tests address
`the appropriate attributes for identity, purity and assay; and the proposed acceptance criteria are
`adequately justified. The analytical methods are described in sufficient detail and have been
`shown to be valid for their intended use at the site of use. Acceptable reference standards have
`been developed for testing.
`
`The submitted stability data is sufficient to support the proposed 24-month expiration dating
`period with storage at controlled room temperature.
`
`All CMC issues were resolved in the first review cycle, however the site proposed for drug
`product manufacture and testing failed its cGMP inspection and a Complete Response was
`issued. The resubmission proposed a new site for manufacture and multiple contract laboratories
`for testing. Revisions to the manufacturing process and analytical methods due to the site
`changes were introduced. The release and stability specifications are unchanged. Complete and
`acceptable CMC information has been provided to support approval of the new manufacturing
`and testing sites. The proposed sites have been found to meets cGMP requirements, however an
`overall conclusion by DC for the application is still pending.
`
`B.
`
`Description of How the Drug Product is Intended to be Used
`
`CMC Review 03
`
`Reference ID: 3332239
`
`Page 8 of 45
`
`

`

`
`
`Executive Summary Section
`
`Injectafer® is a parenteral iron replacement product indicated for the treatment of iron deficiency
`anemia in patients with intolerance to oral preparations or chronic kidney disease. The dosage of
`Injectafer® is expressed as mg of elemental iron (HI).
`
`For iron deficiency anemia, the reconnnended dose is 15 mg/kg body weight up to a single dose
`of 750 mg administered on two occasions at least 7 days apart. Drug is administered as either an
`undiluted slow IV push at 100 mg/minute or by drip infusion diluted in 250 mL normal saline
`administered over 15 minutes. For stability reasons, dilutions to concentrations less than 2 mg
`iron/mL are not permissible.
`
`For hemodialysis dependent chronic kidney disease, the recommended dose is m" mg
`administered as undiluted IV push into the venous line of the dialyzer for 8consecutive
`treatment sessions
`
`C.
`
`Basis for Approvability or Not-Approval Recommendation
`
`The CMC information for drug substance is provided by reference to Vifor’s type H DMF 16967
`which has been reviewed and found adequate to support approval of this application. Complete
`and adequate CMC information has been provided to assure the quality and stability of the drug
`product.
`
`The Division of Medication Error Prevention and Analysis (DIVIEPA) has no objections to the
`use of the proposed proprietary name Injectafer®.
`
`CMC cements on the proposed vial and cartons labels and the package insert are pending
`internal FDA labeling meetings.
`
`An overall recommendation from CC for the application is still pending.
`
`III. Administrative
`
`A.
`
`Reviewer’s Signature: (See appended electronic signature page)
`
`William M. Adams
`
`CMC Reviewer/Branch II/DNDQA I/ONDQA
`
`B.
`
`Endorsement Block:
`
`Ali al Hakim, Ph.D.
`Chief/Branch II/DNDQA I/ONDQA
`
`C.
`
`CC Block: entered electronically in DFS
`
`DHP/RPM/ABaird
`
`DNDQA I/PMQ/J.Martin
`ONDQA I/CMC Lead/J.Brown
`36 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`CMC Review 03
`
`Reference ID: 3332239
`
`Page 9 of 45
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM M ADAMS
`06/26/2013
`
`ALI H AL HAKIM
`06/26/2013
`
`Reference ID: 3332239
`
`

`

`July 9, 2012
`
`Sue-Ching Lin, CMC Reviewer
`
`NDA 203565
`
`Final CMC recommendation for NDA 203565
`
`TO:
`
`SUBJECT:
`
`
`NDA 203565 for Injectafer® (ferric carboxymaltose injection) was initially submitted on
`30-Sep-2011 and was granted a standard review by the Agency. Chemistry Review #1
`(dated 08-Jun-2012) recommended approval of NDA 203565 pending the receipt of an
`overall acceptable recommendation from the Office of Compliance.
`
`This memo serves to update that determination. The Office of Compliance issued an
`overall withhold recommendation for this application on 05-Jul-2012. Accordingly, from
`a CMC perspective, approval of NDA 203565 cannot be recommended until any related
`deficiencies are resolved.
`
`
`
`
`
`
`
`
`
`
`MEMORANDUM
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`DATE:
`
`FROM:
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3156062
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SUE CHING LIN
`07/09/2012
`
`JANICE T BROWN
`07/09/2012
`
`Reference ID: 3156062
`
`

`

`
`
`NDA 203565
`
`Inj ectafer®
`(ferric carboxymaltose injection)
`
`Luitpold Pharmaceuticals, Inc.
`
`Sue-Ching Lin
`
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`Branch II
`
`Chemistry, Manufacturing, and Controls (CMC)
`Review of Original NDA
`For the Division of Hematology Products
`
`Reference ID: 3142758
`
`

`

` CMC REVIEW OF NDA 203565
`hm V
`
`Table of Contents
`
`CMC Review Data Sheet .........................................................................................4
`
`The Executive Summary .........................................................................................9
`
`I. Recommendations ...................................................................................................................... 9
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 9
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable ................................................................................................... 9
`
`II. Summary of CMC Assessments ................................................................................................ 9
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 9
`
`B. Description of How the Drug Product is Intended to be Used ....................................................... 10
`
`C. Basis for Approvability or Not-Approval Recommendation ......................................................... 11
`
`III. Administrative.......................................................................................................................... 12
`
`CMC Assessment.................................................................................................... 13
`
`I. Review Of Common Technical Document—Quality (Ctd—Q) Module 3.2: Body Of Data ....... 13
`
`S. DRUG SUBSTANCE .................................................................................................................... 13
`S. 1
`General Information ........................................................................................................................ 13
`S. l . l
`Nomenclature ............................................................................................................................................. 13
`8.1.2
`Structure..................................................................................................................................................... 13
`
`S 1.3
`S.2
`8.2.1
`
`General Properties ...................................................................................................................................... 15
`Manufacture .................................................................................................................................... 16
`Manufacturers ............................................................................................................................................ 16
`
`8.2.2
`8.2.3
`
`8.2.4
`8.2.5
`
`Description of Manufacturing Process and Process Controls..................................................................... 16
`Control of Materials ................................................................................................................................... 16
`
`Controls of Critical Steps and Intermediates.............................................................................................. 16
`Process Validation and/or Evaluation ........................................................................................................ 16
`
`8.2.6
`8.3
`8.3.1
`
`Manufacturing Process Development ........................................................................................................ 16
`Characterization .............................................................................................................................. 16
`Elucidation of Structure and other Characteristics ..................................................................................... 16
`
`8.3.2
`8.4
`8.4.1
`8.4.2
`8.4.3
`8.4.4
`8.4.5
`8.5
`
`8.6
`s.7
`8.7.1
`8.7.2
`s 7.3
`
`Impurities ................................................................................................................................................... 17
`Control of Drug Substance .............................................................................................................. 17
`Specification .............................................................................................................................................. 17
`Analytical Procedures ................................................................................................................................ 21
`Validation of Analytical Procedures .......................................................................................................... 22
`Batch Analyses .......................................................................................................................................... 22
`
`Justification of Specification.............................. 23
`Reference Standards or Materials ................................................................................................... 23
`
`Container Closure System............................................................................................................... 24
`Stability ........................................................................................................................................... 24
`Stability Summary and Conclusions .......................................................................................................... 24
`Postapproval Stability Protocol and Stability Commitment ....................................................................... 24
`Stability Data ............................................................................................................................................. 24
`
`Reference ID: 3142758
`
`Page 2 of 74
`
`CMC Review #1
`
`

`

`""5“.
`
`CMC REVIEW OF NDA 203565
`
`“Tent
`
`P. DRUG PRODUCT ........................................................................................................................ 24
`
`Description and Composition of the Drug Product .........................................................................24
`RI
`Pharmaceutical Development..........................................................................................................25
`P.2
`Components of the Drug Product............................................................................................................... 26
`P.2.l
`P.2.l.l Drug Substance .......................................
`26
`
`P.2.l.2 Excipients ...................................................................................................................................................... 26
`P.2.2
`Drug Product .............................................................................................................................................. 27
`P.2.2.l Formulation Development ...........
`27
`
`R222 Overages ............................................................
`27
`P.2.2.3 Physicochemical and Biological Properties ................................................................................................... 27
`P.2.3
`Manufacturing Process Development ........................................................................................................ 27
`P.2.4
`Container Closure System.......................
`29
`
`P25
`Microbiologi