CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-660
`
`CHEMISTRY REVIEW! S!
`
`
`
`

`

`
`
`NDA 21—660
`
`Abraxane (Paclitaxel Protein Bound
`Particles for Injectable Suspension) for
`Injectable Suspension, 100 mg
`
`American Bioscience, Inc.
`Division of American Pharmaceutical Partners,
`
`Inc.
`
`Yung-Ao Hsieh, Ph.D.
`
`Division of Oncology Drug Products
`
`
`
`

`

`Table of Contents
`
`...............................................................................................
`
`2
`
`Chemistry Data Sheet
`
`.........................................................................................
`
`3
`
`
`
`
`The Executive Summary
`
`.....................................................................................
`
`6
`
`I.
`
`Recommendations ............................................................................................
`
`6
`
`A. Recommendation and Conclusion on Approvability
`
`--------------------------------
`
`6
`
`B. Recommendation on Phase 4 Commitments, Agreements and/or Risk
`Management Steps, if Applicable
`...........................................................
`
`II.
`
`Summary of Chemistry assessments
`
`............................................................
`
`A. Description of the Drug Product and 5mg Substance
`
`-------------------------------
`
`B. Description of How the Drug Product is to Be Used
`
`-----------------------------
`
`C. Basis for Approvability or Not—Approval Recommendation
`
`---------------------
`
`11], Administrative
`
`............................................................................................
`
`A. Reviewer’s Signature
`
`.................................................................................
`
`B. Endorsement Block
`
`...............................................................................
`
`(3, cc Block
`
`................‘ ..................................................................................
`
`6
`
`6
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`6
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`6
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`6
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`7
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`7
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`7
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`7
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`Chemistry Assessment
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`.........................................................................................
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`9
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`Page 2 of 72
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`I.
`
`Review of Common Technical Document — Quality (Ctd—Q) Module 3.2:
`Body of Data
`................................................................................................
`
`................................................................................
`Paclitaxcl [Indena]
`S
`3.1 General Information ................................................................................
`
`5,2 Manufacture ............................................................................................
`
`3.3 Characterization of Paclitaxel
`
`.................................................................
`
`8.4 Control of Paclitaxel ...............................................................................
`
`8.5 Reference Standards
`
`S_6 Container/closure System of Paclitaxel
`8.7 Stability of Paclitaxel
`
`..................................................
`
`9
`
`9
`9
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`9
`
`10
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`10
`
`21
`
`22
`22
`
`24
`Abraxane (paclitaxel) for Injectable Suspension -------------------------------------
`P
`P_l Description and Composition of Abraxane ............................................. 24
`P2 Pharmaceutical Development of Abraxane, 100 mg/vial
`-----------------------
`30
`P.3 Manufacture ............................................................................................
`39
`
`P4 Control of Excipients ..............................................................................
`[3.5 Control of Abraxane ...............................................................................
`
`P_6 Rgferencg Standard .................................................................................
`
`P] Container Closure System ......................................................................
`{3,8 Stability of Abraxane ..............................................................................
`
`II.
`
`------
`Review of Common Technical Document — Quality (Ctd—Q) Module 1:
`A_ Labeling and Package Insert
`.....................................................................
`
`47
`49
`
`60
`
`60
`64
`
`69
`69
`
`B, Claim of Categorical Exclusion ..................................................................
`
`71
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`
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`Page 3 of72
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`
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`Chemistry Review Data Sheet
`
`1. NDA 21-660
`
`2. REVIEW No.: l
`
`3. REVIEW DATE: 30-Nov-04
`
`4. REVIEWER: Yung-Ao Hsieh, Ph.D.
`
`5. PREVIOUS DOCUMENTS: None
`
`6. SUBMISSIONS BEING REVIEWED:
`Submissions Reviewed
`Document date
`
`NDA 21—660
`NDA 21-660 BC
`
`NDA 21-660 BC
`NDA 21-660 BC
`NDA 21-660 BC
`NDA 21-660 BC
`
`NDA 21—660 BC
`NDA 21-660 BC
`
`NDA 21-660 BC
`NDA 21-660 BC
`
`4-Mar—04
`18-Mar-04
`
`2-Apr—04
`13-Apr-04
`26-Jul-04
`28-Jul-04
`
`25-Aug—04
`12-Oct-04
`
`27-Oct-04
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: American BioScience, Inc.
`
`Address: 2730 Wilshire Boulevard, Santa Monica, CA 90403
`
`Representative: Robert A. Miranda, Director, Drug Regulatory Affairs
`
`Telephone: 310—883-1300
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a)
`b)
`0)
`d)
`
`Proprietary Name: Abraxane
`Non- Proprietary Name: (nab paclitaxel) for Injectable SUSpension
`Code name: ABI-007
`Chem. Type/Submission Priority:
`
`0 Chem. Type: a taxane derivative
`.
`Submission Priority: IS
`
`9. LEGAL BASIS FOR SUBMISSION: N/A
`
`Page 4 of72
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`
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`10.PHARMACOL. CATEGORY: antimicrotubulin agent
`
`11.DOSAGE FORM: lyophilized powder for injection
`
`12.STRENGTH/POTENCT: 100 mg paclitaxel and 900 mg human albumin per vial
`
`13.ROUTE OF ADMINISTRATION: intravenous infiision
`
`l4.Rx/OTC DISPENSED:
`
`
`x Rx
`
`OTC
`
`15.SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`___SPOTS products w Form Completed
`
`_x_ Not a SPOTS product
`
`l6.CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`IUPAC Name:
`
`53,-20-epoxy—1, 2 a , 4, 7B, 1013, 13 a -hexahydroxytax-11-en-9-one 4,10-di-
`acetate 2-benzoate 13-ester with (2R, 3S)—N-benzoyl-3—phenylisoserine
`Non-proprietary Name: Paclitaxel
`Code name: ABI-007
`
`CAS Number: 33069-62-4
`
`MOLECULAR FORMULA: C47H5|NO|4
`MOLECULAR WEIGHT: 853.91
`STRUCTURAL FORMULA:
`
`
`
`
`
`
`
`“--
`
`
`----
`
`Date Review Cements
`
`Completed
`
`Code*
`
`Status
`
`Page 5 of 72
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`
`
`I
`
`III
`
`—-.'-—-
`
`
`
`
`*Action cpdes for DMF Table:
`1-_DMF reviewed
`4-Sufficient information in application
`
`18.CONSULT STATUS:
`
`
`m—
`
`—-—-_
`
`
`1 _—
`—m_—_
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`
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`Page 6 of 72
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`
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`The Chemistry Review for NBA 21-588
`
`The Executive Summang
`
`I.
`
`A. Recommendations:
`
`The application is recommended for approval based on the submitted CMC information and data.
`
`B; Phase IV Commitments:
`There are no recommended Phase IV actions.
`
`II.
`
`Summary of Chemistry Assessments:
`A. Description of the Drug Product and Drug Substance:
`According to the applicant, the drug product is a formulation of “nanoparticles” of paclitaxel coated
`with human albumin and presented as a sterile,
`lyophilized cake of 100 mg of paclitaxel and
`approximately 900 mg of human albumin in a 50 mL ~ glass vial. For administration, each vial is
`reconstituted with 20 mL 0.9% Sodium Chloride Injection, USP to give a suspension of
`“nanoparticles” containing 5 mg paclitaxel per mL.
`It should be noted, however, that the albumin
`bound paclitaxel particle can not be considered as a true nanoparticle (< 100 am), because of its mean
`particle size f_
`-'“
`see detailed discussion under P. 1. Description and Composition of the drug
`product, page 23 of this review) and is more appropriately referred to as fme particles. The drug
`product can be stored at 25°C/60% RH. An expiration dating of 24 months under the recommended
`storage conditions has been granted.
`
`is an antitubulin agent, exhibiting a unique antimitotic activity.
`The active ingredient paclitaxel
`Currently marketed paciitaxel drug products use a Cremophor EL formulation. The drug product is
`manufactured from paciitaxel obtained by
`—-
`Taxus media (commonly known
`as Anglojap Yew). It is a white to off-white powder with poor water solubility. Complete information
`on the drug substance is provided in DMF No.
`-—-‘ A Letter of Authorization (dated 28-Feb-03) to
`grant access to the Agency to refer to the DMF in support of this application is provided in the NDA
`(page 40). Adequate information and data have been provided to support the use of the
`-——
`material in the manufacturing of the ABI-007 drug product.
`
`B. Description of How the Drug Product is Intended to be Used
`Abraxane is indicated for the treatment of patients with breast cancer who have failed initial
`chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior to
`administration, each vial is reconstituted with 20 mL 0.9% Sodium Chloride Injection, USP to give a
`suspension of “nanoparticles” containing 5 mg paclitaxel per mL. The reconstituted suspension
`should be used without further dilution. The drug product is to be administered intravenously over 30
`minutes every 3 weeks. Reconstituted drug product suspension should be used immediately, but may
`be refrigerated at 20-8uC for a maximum of 8 hours if necessary. The recommended dose is 260 mg/mz.
`
`C. Basis for Approvability Recommendation
`This NDA is recommended for approval, from the viewpoint of chemistry, manufacturing and controls
`(CMC) on the basis of the following:
`
`Page 7 of 72
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`

`

`- Adequate information and data have been provided to assure the identity, purity, quality and
`strength of the dmg product.
`Recommended labeling changes will be included in the final printed labling.
`t The CGMP status of the drug substance and drug product manufacturing facilities is acceptable.
`(see Attachment: Establishment Evaluation Report, page 72)
`
`|
`
`Administrative
`
`A. Reviewer’s Signature
`
`Review Chemist, HFD-ISO
`
`Yung-Ao Hsieh, PhD.
`
`B. Endorsement Block
`
`Y. A. Hsieh, Review Chemist:
`Hasmukh Patel, Acting Chemistry Team Leader:
`S. Ryan, Project Manager:
`
`C. CC Block
`
`Original NDA 21-660
`HFD-lSO Div. File
`
`HFD-l SO/YAHsieh
`
`HFD-l 50/HPatel
`
`HFD-lSO/SRyan
`
`Page 8 of 72
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` gq Page(s) Withheld
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`___/§ 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`_.____ § 552(b)(5) Draft Labeling
`
`

`

`
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`—----m—-—--qu|- nun.-n—n-n-un-a—cuu—----un.———--nn--n-—mm—-mm——q-—-—-
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---——u---I.nnun—q.--.n-n—nag-u-n-n-onu-uuununt—-----nmm-mcmm--.n-nn-n—u—nlumm-"m-In-I-n-
`
`/S/
`
`Yung-Ao Hsieh
`12/7/04 10:37:41 AM
`CHEMIST
`
`Hasmukh Patel
`
`12/7/04 12:58:28 PM
`CHEMIST
`
`