CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-344
`
`Chemistry Review(s)
`
`
`
`
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-344
`
`Chemistry Review(s)
`
`
`
`
`
` CHEMISTRY REVIEW
`
`NDA 21-344
`
`REVIEW # 1
`
`FASLODEX (fulvestrant)
`INJECTION
`
`JOSEPHINE M. JEE
`
`REVIEW CHEMIST
`
`DIVISION OF ONCOLOGY
`
`DRUG PRODUCTS
`
`HFD-150/810
`
`CHEMISTRY,
`
`MANUFACTURING AND
`
`CONTROLS REVIEW
`
`
`
`
`
`
`
`Table of Contents
`
`Table of Contents .II.......... IIIIIIIIIIIIIIIOOOOIIIOCCID-OOODODCOOIOII'.I...D.0......IDIDIOODIDCIOOIOIIOOOOIOOOOOOI. 2
`
`Chemistry Review Data Sheet .....
`
`........
`
`..........
`
`The Executive Summary ..............
`
`...................
`
`3
`
`7
`
`1. Recommendations ..................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable ................................................................................................... 7
`
`II. Summary of Chemistry Assessments ........................................................................................ 7
`
`A. Description of the Drug Product(s) and Drug Substance(s).............................................................. 7
`
`B. Description of How the Drug Product is Intended to be Used .......................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 8
`
`III. Administrative .......................................................................................................................... 8
`
`A. Reviewer’s Signature ........................................................................................................................ 8
`
`B. Endorsement Block ........................................................................................................................... 8
`
`C. CC Block ........................................................................................................................................... 8
`
`\
`
`
`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`NDA 21-344 Review #1 FASLODEX (fulvestrant) Injection
`
`Chemistry NDA Review Data Sheet
`
`1. NDA 21-344
`
`2. REVIEW #: 1
`
`3. REVIEW DATE:
`
`l6-JAN-2002
`
`4. REVIEWER: JOSEPHINE M. JEE
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Original 1ND . 5—.
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissionts] Reviewed
`Original (Vol. 1.1 — 1.10)
`Amendment [BC]
`Amendment] [SU]
`Amendment [BM]
`Amendment [BM]
`Amendment] [BS]
`Amendment [C]
`Amendment [BP
`Amendment [BC]
`Amendment [BL]
`Amendment [BP]
`Amendment ]BP]
`Lab. Insert Rev.
`
`Document Date
`
`06-DEC-1996
`
`Document Date
`28-MAR-2001
`19-JUL-2001
`20-JUL-2001
`09-AUG-2001
`28-AUG-2001
`13-SE P-2001
`18-OCT-2001
`29~OCT-2001
`09-Nov-2001
`06-DEC-2001
`11-DEC-2001
`14—DEC-2001
`06-MAR-2002
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`1800 Concord Pike
`
`IPR Pharmaceuticals, Inc.
`
`PO. Box 8355
`
`Wilmington, DE 19803-8355
`
`
`
`
`
` CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`NDA 21-344 Review #1 FASLODEX (fulvestrant) Injection
`“
`'
`' '
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`
`FASLODEXTM
`
`b) Non-Proprietary Name (USAN): 70t-[9-[(4,4,5,5,5Pentafluoropentyl)su1finy]]nonyl]estra-
`1,3,5(10)-triene-3,l7B-diol
`c) Code Name/# (ONDC only): (ICI [82,780, ZD9238, fulvestrant)
`d) Chem. Type/Submission Priority (ONDC only):
`0 Chem. Type:
`1
`0 Submission Priority:
`S
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`FASLODEX (IM) Injection, 250 mg/5 mL, [PR Pharmaceuticals, Inc.
`
`10. PHARMACOL. CATEGORY:
`
`Antiestrogen (Treatment of Breast Cancer)
`
`11. DOSAGE FORM:
`
`Intramuscular Injection
`
`12. STRENGTH/POTENCY:
`
`250 mg/mL
`
`l3. ROUTE OF ADMINISTRATION:
`Intramuscular
`
`l4. Rx/OTC DISPENSED:
`
`_X__Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEMIINoteZI I:
`N/A
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`SW CF,CF, HO
`
`?_
`
`C32H47FSOJS
`MW: 606.77
`70t-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-l ,3,5( l 0)-triene-3, l 7fi-dio]
`
`
`
`
`
` CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`NDA 21-344 Review #I FASLODEX (fulvestrant) Injection
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`ITEM
`"OLDER REFERENCED
`
`2
`
`STATUS
`
`REVIEW
`COMPLETE
`o
`
`1
`
`Information
`
`Request Letter
`
`
`was sent to
`holder on
`3/6/02
`
`17-Jan-02
`
`
`
`Need to
`provide tests
`and specs.
`For primary
`packaging
`materials
`
`TY“I
`
`-
`
`;__ I
`I
`
`,
`
`‘
`
`I ‘ ——
`
`COMMENTS
` i
`
`;
`
`I
`
`I
`
`|
`
`_ -— h
`
`-
`
`a
`
`2000
`
`"
`
`Adequate
`
`15-Jan-02
`
`3
`
`Adequate
`
`2000
`
`28-Aug-
`
`2000
`
`‘ Action codes for DMF Table:
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 - DMF not available
`
`7 — Other (explain under "Comments")
`
`2Adequate, Inadequate, or N/A (There is enough data in the application. therefore the DMF did
`not need to be reviewed)
`
`’
`
`Other Documents:
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`
`
`
`
`
`
`Chemistry Assessment Section
`NDA 21-344 Review #1 FASLODEX fulvestrant
`ln'ection
`
`_II_ IND —>
`
`FASLODEX In'ection
`
`18. STATUS:
`
`ONDC:
`CONSULTSI CMC
`RELATED REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`Peilin Yam. PhD.
`I§_-_— Melissa Garcia
`Lilliam A. Rosario. Ph-D-
`Gene Williams, PhD.
`
`
`
`Acce-table
`
`not acceptable by
`OPDRA
`Methods Validation Imam——
`OPDRA
`“Does not recommend
`15-JAN-2002
`FASLODEX as TM
`
`15-JAN 2002
`
`Nora Roselle, PharmD.
`
`Nora Roselle. PharmD
`
`29-JAN—2002
`Accetable
`"' HFD-150 has decided not to follow OPDRA's recommendation.
`
`avid Husson, Ph.D.
`
`18-JAN-2002
`
`ose.hine M. Jee
`
`
`
`
`
`
`
`Chemistry Assessment Section
`NDA 21-344 Review #1 FASLODEX (fulvestrant) Injection
`
`The Chemistry Review fer NDA 21-344
`
`The Executive Summafl
`
`1.
`
`Recommendations
`
`A.
`
`B.
`
`Recommendation and Conclusion on Approvability
`It is recommended that this application be approved. The PA] is acceptable by
`the Office of Compliance on Jan. 10, 2002. This application provided adequate
`CMC information. There are some minor administrative issues, such as providing
`the regulatory specifications of the fulvestrant drug substance and fulvestrant drug
`product for the stability studies; the reprocessing for both drug substance and drug
`product (commitment to notify the Agency), certificate of analyses from the
`suppliers of the container closures used in the drug product; and revision of the
`carton label, container label, and package insert. The regulatory specifications for
`both drug substance and drug product are on their stability data reports, but not as
`a cited document. Overall, these issues are minor, do not affect the safety or
`efficacy of FASLODEX and will be provided as postapproval agreements.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`Approval is recommended from a CMC point of view. However, there is some
`information listed in Section A that needs to be provided as postapproval
`agreements.
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`l-‘ASLODEXTM is a sterile, clear, colorless to yellow, viscous, oily solution for
`deep intramuscular (IM) injection in a 5 mL pre-filled syringe or two 2.5 mL pre-
`filled syringes (PFS) to deliver, as long acting (LA) injection. FASLODEX contains
`50 mg per m1. fulvestrant and is administered once a month. Fulvestrant drug
`substance is a white powder with a molecular weight of 606.77. Fulvestrant contains
`6 asymmetric carbon atoms and stereogenic sulfoxide in the side chain.
`\
`
`_
`
`.
`
`.
`
`\
`\
`
`'
`
`
`
`
`
`
`
`Chemistry Assessment Section
`NDA 21-344 Review #1 FASLODEX (fulvestrant) Injection
`B. Description of How the Drug Product is Intended to be Used
`The drug product is intended to be used intramuscularly. The maximum recommended
`monthly dose is 250 mg and it is administered by a health practitioner. Based on
`supportive data of ‘month long-term stability data, the requested“ month
`expiration dating is acceptable.
`
`C. Basis for Approvability or Not-Approval Recommendation
`FASLODEX has an acceptable GMP inspection. From a CMC perspective,
`AstraZeneca provided information to support the adequacy of fulvestrant drug
`substance and drug product. The physical and chemical characteristics, impurity
`profile, and the stability for fulvestrant drug substance are adequately demonstrated in
`this application. The HPLC method provided for an acceptable separation of
`fulvestrant from its impurities and degradants. The I" method is capable of
`separating solvents that may be potential organic solvent impurities. The validation
`of HPLC and - methods demonstrated the ruggedness and specificity of these
`methods. They also provided acceptable validation and justification for the remaining
`analytical methods used in the determination of fulvestrant drug substance and drug
`product.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`.—
`
`3. Endorsement Block
`
`Josephine lee/Date: 18-JAN-2002
`Josephine Jee/ Rev. lO-APR-2002
`Josephine Jee/ Rev. 16-APR-2002
`Richard Lostritto/Date:
`
`Amy Baird/Date
`
`C. CC Block
`
`Orig. NDA 21-344
`HFD-l SO/Division File
`HFD-l 50/JJee
`HFD-l 50/ABaird
`l-[FD- l SO/RLostritto
`HFD—8lO/JSimmons
`
`
`
`
`
`Redacted
`
`‘53
`
`peges of trade
`
`secret and/or
`
`confidential
`
`
`
`
`
`
`
`Chemistry Assessment Section
`NDA 21-344 Review #1 FASLODEX (fulvestrant) Injection
`
`B. Environmental Assessment Or Claim 01' Categorical Exclusion
`Vol. 1.5, section “Environmental Assessment”, p.l
`IPR Pharmaceutical states they have no knowledge of any exceptional circumstances
`exist that would require additional controls to be imposed on the use of FASLODEX in
`order to protect the environment..
`IPR Pharmaceuticals requests that NDA 21-344 for FASLODEX be qualified for a
`categorical exclusion based on See. 25.3l(a) and (b) wherein the action increases the use
`of the active moiety, but the estimated concentration of the substance at the point of entry
`into the aquatic environment will be below 1 part per billion (ppb).
`
`Evaluation: Adequate.
`
`
`
`
`
` .' CHEMISTRY REVIEW TEMPLAT ,
`Chemistry Assessment Section
`NDA 21-344 Review #1 FASLODEX (fulvestrant) Injection
`
`11]. List Of Deficiencies To Be Communicated
`
`We have the following comments regarding fulvestrant drug substance:
`
`1. The proposed specification for “'—
`assay is I-iP/o w/w and the total organic impurities is —%. The applicant should
`provide information on additional impurities or degradants that may contribute to
`the remaining-%.
`
`_—-——-—i-
`2. The proposed assay specification for
`~ is —% w/w and the total organic impuritiesIs specified as-Vo w/w
`maximum. Please provide any impurities or degradantsIn :1— ;that may
`contribute to the remainingo-‘I w/w.
`
`.
`3. The proposed assay specifications for . fl ‘
`range from -% w/w.
`__—— is listed as an impurity at ‘Wo w/w
`maximum. Please provide information on degradants or impurity that may
`contribute to the remaining ' %.
`
`4. The proposed assay specifications for —-§_.
`assay range from
`_—"
`.This specification is rather broad it should be
`tightened to better reflect actual batch data.
`
`assay is
`5. The proposed specifications for. ——
`specified as Ai%. The applicant should provide the impurities that may
`contribute to the remaining —-%.
`
`’i---—
`6. Please revise the drug substance specification for water content,
`—‘ specific optical rotation, microbial content, and endotoxins to
`reference appropriate USP/NF methods.
`
`7. The limit for '. h should be
`lowered to NMT d/o since it was not detected in any batches of fulvestrant drug
`substance studied.
`
`8. Please submit adequate documentation on the ‘ bags which indicates
`that it complies with 21 CFR. Please describe further, the materials of construction
`for the ’ _____ lid used for bulk packaging of fulvestrant drug
`substance and acceptance criteria, to support use of these materials.
`
`9. Please provide the stability regulatory specification and tests for fulvestrant
`drug substance.
`
`10. Please revise the specification for identification test to the IR absorption spectrum
`
`
`
`
`
`
`
`Chemistry Assessment Section
`NDA 21-344 Review #1 FASLODEX (fulvestrant) Injection
`of fulvestrant sample compares with that obtained from the Fulvestrant
`Reference Standard.
`
`1 1. Please revise the Fulvestrant Reference Standard specification for water content,
`"' "'
`_
`.
`, specific optical rotation, microbial content,
`and endotoxins to reference appropriate USP/NF methods.
`
`12. Please include tests and limits for Total Organic Impurities in the Specifications
`for Fulvestrant Reference Standard.
`
`13. Please provide a commitment that no . —— will be performed without
`notification to the Agency.
`
`We have the following comments for Faslodex Injection:
`
`'7“ submitted by Vetter. —-
`1. We have reviewed Drug Master File (DMF)
`GmbI-I & Co. KG
`.-—-—_—
`and identified several comments. The
`nature of these comments will be communicated to the DMF holder separately.
`
`2. Please include tests for optical clarity, viscosity, extractables I—D V and free
`fatty acid content in the specifications for fulvestrant drug product as they are
`provided in the stability study of fulvestrant drug product.
`
`3. Please provide the complete regulatory specifications for the stability study of
`FASLODEX Injection.
`
`4. Please provide the chemical resistance test and results for the Type I glass components
`(syringe barrel) as per current USP <661>.
`
`5. Given the solvent power of the drug product vehicle, please provide results for
`a one-time characterization of extractables from the rubber container-closure
`
`components into the formulation
`
`6. Please provide the test results for syringe barrel, rubber plunger and rubber
`tip-cap as per tests and specifications listed in Vol. 1.5, Container Closure
`Section of this application.
`
`7. Please submit certificate of analyses from the suppliers of container closure for
`batches of drug product submitted in this application.
`
`8. Please provide a commitment that no _.—-
`performed without notification to the Agency.
`
`Faslodex Injection will be
`
`
`
`
`
`
`
`Chemistry Assessment Section
`NDA 21-344 Review #1 FASLODEX (fulvestrant) Injection
`
`We recommend the following revisions to the Carton Label (2.5 mL and 5 mL) and
`Syringe Label:
`
`1. Please revise the list of inactive ingredients in the Carton Label and list as: Alcohol,
`USP; Benzyl Alcohol, NF; Benzyl Benzoate, USP; and Castor Oil, USP.
`
`2. Please include the following statement on the Syringe Label: RX only.
`
`
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/5/
`
`Josephine Jee
`4/17/02 05:03:56 PM
`CHEMIST
`
`Richard Lostritto
`4/22/02 01:32:45 PM
`CHEMIST
`
`
`
`
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