CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-572
`
`Chemistry Review(s)
`
`

`

`CHEMISTRY REVIEW
`
`NDA 21-572.
`
`CUBICIN®. '
`
`(daptomycin for injection)
`
`Cubist Pharmaceuticals, Incorporated
`
`Reviewed by
`
`Zi-Qiang Gu, Ph.D.
`Division of Antiviral Drug Products
`
`

`

` CHEM]STRY REVIEW
`
`Table of Contents
`
`The Executive Summary9
`
`1.
`
`Recommendations....................................... .....9
`
`Recommendation and Conclusion on Approvability........................................'....................................... 9
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable;....................................................................................................-..... 9
`
`Summary of Chemistry Assessments
`
`......9
`
`Description of the Drug Product(s) and Drug Substance(s) ...................................................................... 9
`
`Description offlow the Drug Product is Intended to be Used ................................................................. 10
`
`Basis for Approval, Approvable or Not-Approval Recommendation ............................................... 11
`
`Administrative........ .....
`
`......
`
`.....
`
`.........
`
`......11
`
`Ren'ewer‘s Signature .....................................................I..................................................................... 11
`
`Endorsement Block ........................................................................................................................... 11
`
`ChemistryAssessment12
`
`l.
`
`DRUG SUBSTANCE ...... ......
`
`.............. . .....................
`
`........... ...........12
`
`Description & Characterization ......................................................................................................... 12
`
`a.
`b.
`
`Description .......................................................................... ...................................... 12
`Characterization / Proof 0f Structure.................................................................................. 13
`
`Manufacturer ............................................................................................................................. 22
`
`Synthesis / Method Of Manufacture.............................................................-..................................... 22
`
`3.
`
`b.
`
`c.
`
`d.
`
`Starting Materials - Specs & Tests ............................................................................ 22
`
`_
`
`Solvents, Reagents, etc. .................................................................................................... 24
`
`Flow Chart................................_...................................................................................................‘........ 33
`
`Detailed Description ........................................................................................... 33
`
`Process Controls .........................'............................................................................... 38
`
`I 3.
`
`b.
`c.
`
`Reaction Completion IOther ln-Process Tests ........................................................ 38
`
`Intermediate Specs 8.- Tests .....................................................................-.... 38
`Manufacturing Process DeveIOpment ........................................................................................ 59
`
`......_............................;..................................................................... 63
`Reference Standard"'I’f'“
`
`
`

`

`CHEMISTRY REVIEW
`
`a.
`
`1).
`
`Preparation ................................................................................................................................. 63
`
`Specifications ................................................................................................................... 63
`
`Regulatory Specifications IAnalyfical Methods ..................................................................................... 64
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`Drug Substance Specifications & Tests ...................................................................... 64
`
`Batch Analysis Data ................................................................................................ 68
`
`Analytical Methods and Validation: ...................................................................... 69
`
`Purity Profile .....-......................-.................'............................................................... 75
`
`Microbiology......._......................................-..............-.........................l................................... 77
`
`Container/Closu re System for Drug Substance Storage ....................................................................... 78
`
`Drug Substance Stability"............................................................................................... 81
`
`Components/Composition ...-........................................................................................................ 87
`
`Specifications & Methods for Drug Product Ingredients -.....4....................................................... 87
`
`a.
`
`b.
`
`Active Ingredient(s)............................................................................................................... 87
`
`Inactive Ingredients.......................................................................................................... 88
`
`Manufacturer ..................L............................................................................................................... 89
`
`Methods of Manufacturing and Packaging .........L............................................................................. 90
`
`a.
`
`b.
`
`Production Operationsd......................................................................................................... 90
`
`Reprocessing Operations ..................................................................................................... 100
`
`Regulatory Specifications and Methods for Drug Product...._.............:.................................................. 100
`
`2.
`
`b.
`c.
`
`(1.
`
`Sampling Procedures ............................................................................................................... 100
`
`Regulatory" Specifications and Methods ........................................................................ 100
`Batch Analysis Data .......................................................................................................... 102
`
`Analytical Methods and Validation: ................................................................................ 102
`
`Container/Closure System...........................................-.................................................»..................“...“... 104
`
`Microbiology-......................-.........................._............................................................................. 106
`
`Drug Product Stability...”....................................................l......................................... 107
`
`IN VESTIGATIONAL FORMULATIONS
`
`.......................1 15
`
`ENVIRONMENTAL ASSESSMENT] 15
`
`METHODS VALIDATION
`
`......
`
`........
`
`............1 15
`
`II.
`
`III.
`
`IV.
`
`V1.
`
`LABELING
`
`.....
`
`.....116
`
`VII.
`
`ESTABLISHMENT INSPECTION
`
`.....
`
`................
`
`.................l 18
`
`

`

` CHEMISTRY REVIEW
`
`Vlll. DRAFT DEFICIENCY LETTER .......................................................................... 122
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA # 21-572
`
`2. REVIEW # l
`
`3. REVIEW DATE: August 1, 2003
`
`4. REVIEWER: Zi-Qiang Gu, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`{ND 57,627 (Original)
`IND 57,627, Serial No. 57
`IND 57,627, Amendment 03]
`IND 57,627, Amendment 074
`
`Sept. 2000
`1999 Annual Report
`2000 Annual Report
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission( 5) Reviewed
`NDA 21-572
`NDA 21-572/Response for information request
`NDA 21-572/BC, Stability update
`NDA 21-572/Response for information request
`NDA 21-572/Response for information request
`NDA 21-572/Response for information request
`NDA 21—572/Response for information request
`NDA 21-572/Response for information request
`NDA 21-572/Response for Label
`
`Document Date
`Dec. 20, 2002
`March 27, 2003
`March 3], 2003
`April 11, 2003
`May 15, 2003
`July 3, 2003
`August 5, 2003
`September 3, 2003
`September 11, 2003
`
`Page 5
`
`

`

` CHERIISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`;
`
`Cubist Pharmaceuticals, Inc.
`
`Address:
`
`65 Hayden Avenue, Lexington, MA 02421
`
`Representative:
`
`David H. Schubert
`
`Telephone:
`
`7]8-860~8455
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: CUBUCIN® (proposed)
`b) Non-Proprietary Name (USAN): Daptomycin
`c) Code Name/iiI (ONDC only): CB-IO9187, LYI46032
`d) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 1
`
`0 Submission Priority: P
`
`9. LEGAL BASIS FOR SUBMISSION: N/A
`
`10. PHARMACOL. CATEGORY: Antibiotics
`
`I I. DOSAGE FORM: Injection
`
`I2. STRENGTH/POTENCY: 250 mg and 500 mg
`
`13. ROUTE OF ADMINISTRATION: IV
`
`14. Rx/OTC DISPENSED: ARX
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`fl
`
`Page 6
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`l6. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name:
`
`N-Decanoyl-L—tryptophyl-L-asparaginyl-L-aspartyl-L-
`threonylglycyl-L-omithyl-L-aspanyl~D-alany1-L-
`asparty1glycyl-D-seryl-Ihreo-3-methyl-L-glutamy1-3-
`anthraniloyl-L-alanine el-lactone
`
`Chemical Structure:
`
`:
`
`no :2
`
`1:
`'1”
`
`12 H).
`“Ci: 0
`%
`E Ja
`
`‘0‘
`
`‘1
`
`o
`
`0
`
`o
`
`'
`
`.‘
`
`15
`
`a
`
`3
`2
`.c
`
`'°"‘° :
`
`1
`0
`”Lo” :‘rc” :
`
`:7
`
`_r‘~..
`
`Molecular Formula:
`
`C72H101Nl7026
`
`Molecular Weight:
`
`1620.67
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`HOLDER
`
`ITEM
`REFERENCED CODE
`
`,
`
`STATUS
`
`2
`
`DATE
`REVIEW
`COMPLETED
`
`COMMENTS
`
`S. C. Poe
`
`
`
`
`4/14/2003
`
`Y. Yang and
`S. P. Peri
`
`
`
`
`\'
`\
`' '----S. Simek
`
`- lass vials
`
`' Action codes for DMT Table:
`_.
`.‘___“,
`._-~..,
`
`Page '_7
`
`

`

` CHED'IISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DM]:
`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")
`
`zAdequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents:
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`__— '
`
`l8. STATUS:
`
`
`CONSULTS/ CMC
`
`RELATED
`RECOMMENDATION
`
`
`REVIEWS
`
`
`DATE
`
`REVIEWER
`
`
`
`
`
`
`
`
`
`
`
`
`__
`
`CUBlCIN is recommended
`b DAIDP
`
`LNC _—
`_w-
`ODS
`Not recommended
`9/12/03
`
`EA
`
`Microbiolo 3
`
`Exclusion Accetable
`
`
`
`A . .roval
`
`9/12/03
`
`9/12/03
`
`Page 8
`
`

`

` CHENHSTRY REVIEW
`
`Executive Summary Section
`
`The Chemistry Review for NBA 21-245
`
`The Executive Summtyy
`
`I.
`
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The Chemistry, Manufacturing and Controls information provided for the drug substance
`and the drug product (CUBICINTM, daptomycin for injection) are adequate. Therefore, this
`NDA is recommended for approval for CUBICINTM (daptomycin) for injection, with
`recommendation of an expiration dating period of 24 months when stored at 2—8°C.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`N/A
`
`4"‘
`
`ll.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug substance (DS), deptomycin (LY146032) is reportedly a novel bactericidal
`lipopeptide that represents a new class of natural product antibiotics. Daptomycin is
`indicated for the treatment of complicated skin and skin structure infections caused by
`susceptible'strains of the following Gram-positive microorganisms: Staphylococcus aureus
`(including methicillin-resistant strains); Streptococcus pyogenes, Streptococcus agalactiae;
`Enterococcusfaecalis (vancomycin-susceptible strains only);
`-—s
`'o
`. The mechanism of action appears to involve calcium-dependent insertion
`of the decanoyl side chain into the bacterial membrane followed by depolarization of the
`membrane with concomitant release of K+ ions. These events are tied to rapid,
`concentration dependent killing of Gram-positive Organisms.
`
`Daptomycin, as a new chemical entity, is unique among current antibiotics due to the
`presence of both lipophilic (ie, decanoyl side chain) and hydrophilic (ie, peptide) regions in
`the molecule.
`//
`_
`/'
`difficult,
`’j/\ _
`F’“
`procedures -1_
`substance is .
`
`The manufacturing process for the drug substance is
`'
`_ The purified drug
`
`_
`
`_ /
`/’/
`
`ii
`
`Page 9
`
`

`

` CHEMISTRY REVIEW
`
`Executive Summary Section
`
`Specification for the starting materials and reagents are properly specified, and parameters
`for in-process controls are adequately identified and monitored. The structural
`characteristics of daptomycin have been evaluated by using different spectroscopic and
`analytic techniques, and are in good agreement with literature‘s original assessment,
`Specification ofthe drug substance includes appearance, identification . ’
`concentration and purity v related degradants and impurities (specified, unspecified
`and total), specific rotation, residue on ignition, heavy metals, residual solvents, bacterial
`endotoxins and microbial limits.
`
`The drug substance stability data were generated on batches manufactured at _ W
`using the 1
`._——«’
`' process (24 months at —15°C 1 5°C and at —5°C i 3°C, 3 months at
`5i3°C). The results conformed to the final specification. There are no significant time-
`dependent variation and trend observed. The retest period of v months for drug substance
`isjustified when stored at recommended storage condition of- —/
`
`Drug product, CUBICINTM (daptomycin for injection), is supplied as a sterile, lyophilized
`powder (250 mg and 500 mg) for reconstitution with 0.9% sodium chloride injection, USP.
`There is no excipient usedlin the manufacture of the drtig product. The manufacturing
`process for the drug product includes
`\
`
`\
`
`labeling and packaging.
`
`The regulatory specification for CUBICINTM (daptomycin for injection) is adequately
`established. The primary stability data is provided on six representative batches (3 in the
`250 mg/vial and 3 in the 500 mg/vial) at 5°C i 3°C (24 months), at 25°C: 2°C (24 months)
`and at 40°C ‘_-': 2°C/75%RH (6 months). Statistical evaluation of the primary stability data
`appears to support a shelf-life of. __,__.
`for CUBUClN® (daptomycin for injection) in a
`glass vial with a rubber closure and aluminum seal when stored at the recommended
`storage condition of2°C - 8°C. However, a shelf-life of 24 months stored at 2-8°C is
`recommended for CUBlClNTM (daptomycin for injection) based on overall review of the
`information provided.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The drug product, CUBICINTM (daptomycin for injection), is supplied in single-use vials
`containing either 250 or 500 mg daptomycin as a sterile, lyophilized powder. The contents
`of daptomycin 250 mg vial and 500 mg vial should be reconstituted with 5 ml. and 10 mL
`of 0.9% sodium chloride injection, USP, respectively. Reconstituted daptomycin should be
`further diluted with 0.9% sodium chloride injection, USP to be administered by intravenous
`infusion over a period of 30 minutes. The final concentration ofthe solution for infusion
`should not exceed 20 mg daptomycin/mL. The intended clinical dose regimen is 4 mg/kg
`every 24 hours by 30-minute intravenous (i.v.) infusion to hospitalized patients for 7 to 14
`_ “-2
`
`Page 10
`
`

`

` CHEMISTRY REVIEW
`
`Executive Summary Section
`
`days. A shelf-life of 24 months for CUBICINTM (daptomycin for injection) is
`recommended when stored at 2-8°C.
`
`C. Basis for Approval, Approvable or Not-Approval Recommendation
`
`The NDA submission and amendments ultimately provided adequate information on the
`chemistry, manufacturing and controls for the production of CUBIClNTM (daptomycin for
`injection), 250 mg per vial and 500 mg per vial.
`
`After discussion and negotiation with the applicant, acceptable levels for related substances
`in the drug substance specification were established in conjunction with the
`Pharrnacologyl'l'oxicology reviewer, based on the pre-clinical and clinical data, as well as
`the history data on manufacturing. The analytical methods and validations for the ‘drug
`substance and the drug product are properly documented and appear adequate from
`regulatory perspective.
`
`Pre-approval inspection concluded that all manufacturing, testing and packaging facilities
`were acceptable in CGMP compliance.
`
`The proposed trade name CIDECINTM was concerned for mistaking with the name of a
`_ currently marketed product (CLEOC1N®) by the Agency. Therefore, the applicant has
`proposed five candidate names (CUBICIN,
`_:
`-—-_~———-
`_
`. and
`
`, for evaluation. CUBICINTM is recommended for the trade name for
`daptomycin by DAIDP.
`
`III.
`
`Administrative
`
`A. Reviewer’s Signature
`
`Chemist:
`
`Zi-Qiang Gu, PhD. {Signed electronically in DFS}
`
`B. Endorsement Block
`
`Chemistry Team Leader:
`James Vidra, PhD. {Signed electronically in DPS}
`
`\‘l
`
`Page ll
`
`

`

`Redégted Ill.
`pages bf trade
`
`secfét'and/or
`
`’confidential
`
`commerCi§l_
`
`'infOrmation
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`-
`Zi—Qiang Gu
`9/12/03 01:04:34 PM
`CHEMIST
`
`Jim Vidra
`
`9/12/03 01:09:19 PM
`CHEMIST
`
`l!
`
`