CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`201023
`201023
`
`APPLICA TION NUMBER:
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`CHEMISTRY REVIEW(S)
`CHEMISTRY REVIEWg S)
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`

`

`Application:
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`Stamp Date:
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`itory:
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`R
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`Applicant:
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`FDA CDER EES -'
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`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`Action Goal:
`
`District Goal:
`
`
`24-MAY-2010
`
`NDA 201023/000
`
`31 MAR-2010
`
`30-SEP-201O
`
`SANOFI AVENTIS SPA
`
`
`55 CORORATE DR
`
`
`
`BRIDGEWATER, NJ 08807
`
`
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`I
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`Brand Name:
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`Estab. Name:
`
`Generic Name:
`
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`CABAZITAXEL (XRP6258)
`
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`Priority:
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`Org. Code:
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`1
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`_ 150
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`Product Number; Dosage Form; Ingredient; Strengths
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`001; SOLUTION, CONCENTRATE; CABAZITAXEL; 60MG/1.5ML
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`Application Comment:
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`FDA Contacts:
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`PRIORITY PROSTATE CANCER NDA WITH SHORTENED REVIEW CLOCK- 8 WEEK REVIEW CLOCK. REQUEST
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`COMPLIANCE OVERALL RECOMMENDATION BY 5/24/10 (on 08-APR-2010 by D. MESMER (HFD-800) 301-796-4023)
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`Project Manager
`(HFD-800)
`301-796—4023
`D. MESMER
`X. CHEN
`Review Chemist
`301 -796-1 337
`
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`H. SARKER
`
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`Team Leader
`
`
`(HFD-150)
`
`301-796-1747
`
`Overall Recommendation:
`
`
`ACCEPTABLE
`
`on 03-MAY-2010
`
`
`by M. STOCK
`
`
`(HFD-320)
`
`301-796-4753
`
`a nae-10,1201!) 1:17 PM: 1 ‘
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`FDA'Jconfide'ntlal :- Internal Distribution only; - ,
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`Page-1 of 6' « ‘-
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`FDA CDER EES
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`ESTABLISHMENT EVALUATION REQUEST
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`DETAIL REPORT '
`
`FEI:
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`
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`(b) (4)
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`AADA:
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`(4)
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`(b) (4)
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`Establishment:
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`CFN:
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`DMF No:
`
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`Responsibilities:
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`Estab. Comment:
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`Profile:
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`Milestone Name
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`Comment
`SUBMITTED TO 00
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`OC RECOMMENDATION
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`Milestone Date
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`08-APR-201 0
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`21-APR-2010
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`OAI Status:
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`NONE
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`(b) (4)
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`Request Type
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`Planned Comgletion Decision
`
`
`Reason
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`Creator
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`MESMERD
`
`STOCKM
`ACCEPTABLE
`
`BASED ON FILE REVIEW
`
`
`
`
`Junes1 0532010 1:17 PM”
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`
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`FDA“ Confidential 74 Internal Di'stributionvomy '
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`P'a'ge:2 sot-:6"
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`
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`FDA CDER EES‘
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT '
`FEI: 3002808000
`
`
`CFN: 9610119
`
`AVENTIS PHARMA LTD.
`
`
`9 QUAL JULES GUESDE
`
`
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`VITRY-SUR-SEINE, , FRANCE
`
`(b) (4)
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`DRUG SUBSTANCE LABELER
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`DRUG SUBSTANCE MANUFACTURER
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`DRUG SUBSTANCE PACKAGER
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`DRUG SUBSTANCE RELEASE TESTER
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`DRUG SUBSTANCE STERILITY TESTER
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`AADA:
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`EMAIL FROM ELIZABETH PHILPY ON 4/7/10 INSTRUCTS THAT INFORMATION SUBMITTED FOR BOTH SANOFI-AVENTIS
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`RECHERCHE & DEVELOPPEMENT AT 13 QUAI JULES GUESDE AND SANOFI CHIMIE AT 9 QUAI JULES GUESDE SHOULD
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`BE SUBMITTED UNDER THIS FEI NUMBER, 3002808000. SPONSOR INDICATES AT #13 QUAI JULES GUESDE:
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`MANUFACTURING OF THE DRUG SUBSTANCE FROM (b) (4) AND (b) (4) AND MICROBIAL CONTAMINATION TESTING
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`OF THE DRUG SUBSTANCE
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`AT 9 QUAI JULES GUESDE: TESTING AND RELEASE OF
`(b) (4)
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`TESTING AND RELEASE, PACKAGING AND LABELING OF THE DRUG SUBSTANCE.
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`CONTACT NAME FOR #13 IS :MARIE—PIERRE IMBERT
`
`
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`QUALITY ASSURANCE MANAGER
`
`
`MARIE-PlERRE.|MBERT@SANOFI-AVENTIS.COM
`TEL: 33.1.58.93.88.66
`
`FAX: 33.1.58.93.30.61 (on 07-APR-2010 by D. MESMER (HFD-800) 301-796-4023)
`
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`PLEASE REFER TO FACTS ASSIGNMENT IDS 1157497 AND 1157501, WHICH WERE ISSUED FOR THIS PRODUCT PRIOR
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`TO SUBMISSION DUE TO THE EXPEDITED STATUS OF THE APPLICATION. (on 09-APR-2010 by M. STOCK (HFD-320)
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`301 -796-4753)
`NON-STERILE BULK BY CHEMICAL SYNTHESIS
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`OAI Status:
`
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`
`NONE
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`
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`Milestone Date
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`Reguest Type
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`08-APR-2010
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`Planned Comgletion Decision
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`Reason
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`Establishment:
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`DMF No:
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`Responsibilities:
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`Estab. Comment:
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`Profile:
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`Milestone Name
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`Comment
`8' " ‘ ‘lTTED TO 00
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`SUBMITTED TO DO
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`
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`09-APR-2010
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`Product Specific
`
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`ASSIGNED INSPECTION TO IB
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`16-APR-2010
`
`Product Specific
`
`
`03-MAY—2010
`DO RECOMMENDATION
`
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`EXPEDITED COMPLIANCE REVIEW DONE BY DOUG CAMPBELL.
`
`
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`
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`OC RECOMMENDATION
`
`
`O3-MAY—2010
`
`Creator
`
`MESMERD
`
`STOCKM
`
`JOHNSONE
`
`STOCKM
`
`ACCEPTABLE
`INSPECTION
`
`STOCKM
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`Juner10, 20:10 1:17‘PM' .-
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`
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`FDA‘Co'nfide'ntlaI 5 Internal Distribution On'ly»
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`Page-<5 of 6 l:
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`
`FDA CDE‘R EES
`ESTABLISHMENT EVALUATION REQUEST
`
`
`
`DETAIL REPORT
`FEI: ' 1000541557
`
`
`CFN: 9610433
`
`AVENTIS PHARMA LTD.
`
`
`RAINHAM ROAD SOUTH
`
`
`DAGENHAM, , UNITED KINGDOM
`
`
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE MANUFACTURER
`
`
`
`Establishment:
`
`DMF No:
`
`
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`Estab- Comment:
`
`Profile:
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`Milestone Name
`
`Comment
`SUBMITTED TO GO
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`MANUFACTURING, TESTING AND RELEASE, PACKAGING AND LABELING OF THE DRUG PRODUCTS (CABAZITAXEL
`
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`CONCENTRATE FOR SOLUTION FOR INFUSION AND SOLVENT FOR DILUTION) (on 07-APR-2010 by D. MESMER (HFD-
`
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`800) 301-796-4023)
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`STERILE-FILLED SMALL VOLUME PARENTERAL DRUGS
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`OAI Status:
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`NONE
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`Milestone Date
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`
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`Reguest Type
`
`
`
`08-APR-2010
`
`
`
`Planned Completion Decision
`_
`Reason
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`Creator
`
`MESMERD
`
`STOCKM
`
`JOHNSONE
`ACCEPTABLE
`
`BASED ON FILE REVIEW
`
`
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`
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`ACCEPTABLE
`BASED ON. PROFILE
`
`
`DISTRICT RECOMMENDATION
`
`
`INYARDA
`
`SUBMITTED TO DO
`
`
`
`,
`
`OS—APR-201O
`
`10-Day Letter
`
`
`DO RECOMMENDATION
`
`
`16-APR-201O
`
`
`OC RECOMMENDATION
`
`18-APR-2010
`
`>
`
`’
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`June‘flof-‘ZOJO 1:17PM?
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`FDA cenfidentiaIF‘ Internal Distribution only. "
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`Page-420m
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`FDA CDER‘EES
`
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`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`Establishment:
`
`DMF No:
`
`
`CFN: 9610721
`
`SANOFI AVENTIS PHARMA SA
`
`
`
`
`63480
`VERTOLAYE, , FRANCE
`
`
`(b) (4)
`
`FEI: 1463
`
`
`AADA:
`
`Responsibilities:
`
`INTERMEDIATE MANUFACTURER
`
`
`
`Estab- Comment:
`
`Profile:
`
`(b) <4): FROM BEPIME (RPR106926)
`MANUFACTURING OF
`
`
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`
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`('3) (4) (on 07-APR-2010 by D. MESMER (HFD-800) 301-796-4023)
`TESTING AND RELEASE OF
`
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`NON-STERILE BULK BY CHEMICAL SYNTHESIS
`OAI Status:
`NONE
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`
`
`Milestone Name
`
`Comment
`SUBMITTED TO 00
`
`
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`OC RECOMMENDATION
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`Milestone Date
`
`
`
`Reguest Type
`
`
`
`08-APR-2010
`
`09-APR—2010
`
`
`
`Planned Comgletion Decision
`Reason
`
`Creator
`
`MESMERD
`
`STOCKM
`ACCEPTABLE
`
`BASED ON FILE REVIEW
`
`
`
`
`June‘10;-20,10~1:17 PM “x
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`
`
`FDA’Confldentlalmintemalfllstribution :On'lya
`
`_
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`P219335 of:6 1%
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`
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`Establishment:
`
`CFN:
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`DI.~
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`.«o:
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`Responsibilities:
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`Estab- Comment:
`
`
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`FDA CDER EES ,
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`(b) (4)
`(b) (4)
`
`
`
`(b) (4)
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`(b) (4)
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`'
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`FEI:
`(b) (4)
`
`(b) (4)
`
`AADA:
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`INTERMEDIATE MANUFACTURER
`
`
`MANUFACTURING
`ADDRESS PROVIDED BY APPLICANT:
`
`
`
`SERIPHARM SA (NOVASEP)
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`ESTABLISHMENT NUMBER PROVIDED BY APPLICANT
`
`
`
`
`
`(b) (4)
`
`Profile:
`
`(on OS-APR-2010 by D. MESMER (HFD-800) 301-796—4023)
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`
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`
`
`
`(b) (4)
`
`OAI Status:
`
`
`NONE
`
`
`Milestone Name
`
`Comment
`SUBMITTED TO 00
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`
`
`OC RECOMMENDATION
`
`
`Milestone Date
`
`
`08-APR—2010
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`21-APR-2010
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`Reguest Type
`
`’
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`
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`Planned Comgletion Decision
`
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`Reason
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`_
`
`Creator
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`MESMERD
`
`STOCKM
`ACCEPTABLE
`
`BASED ON FILE REVIEW
`
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`
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`cane/10,4010 1:17 PM?
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`FDA‘Cdnfidemlalz- Internal Distribution-only»
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`Pagez'6~20f‘6*':i ‘
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`ONDQA Division Director’s Memo
`NDA 201-023, JEVTANA (cabazitaxel) Injection
` 40 mg/mL supplied as 60 mg/1.5mL
`Date: 04-JUN-2010
`
`Introduction
`
`JEVTANA (cabazitaxel) Injection is indicated for the treatment of metastatic prostate
`cancer that has progressed after docetaxel-based treatments. The drug product is supplied
`as a non-aqueous solution which is diluted with a co-packaged diluent at the time of
`administration. This pre-mix dilution is then added to normal saline for injection or D5W
`for intravenous infusion. ONDQA recommends approval of this NDA.
`
`Administrative
`
`The original submission of this 505(b)(1) NDA was received 25-FEB-2010 from Sanofi-
`Aventis, Bridgewater, NJ. This priority review was also given a highly accelerated
`review status in light of the critical medical need cited by DDOP.
`
` total of seven CMC amendments were reviewed between 12-MAR-2010 and 28-MAY-
`2010. The NDA is supported by nine DMF’s and by IND 56,999. Consults for PAI
`(EES acceptable -8-APR-2010), PharmTox, and EA are acceptable.
`
`This NDA is recommended for approval from a Chemistry, Manufacturing and
`Controls standpoint.
`
`Drug Substance
`
`The APi is cabazitaxel which contains a nearly stoiciometric molecule of acetone as the
`solvate in the solid (lyophilized) state. The name is:
`benzenepropanoic acid, β -[[(1,1-dimethylethoxy)carbonyl]amino]-α -hydroxy-,
`(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-(acetyloxy)-12-(benzoyloxy)-
`2a,3,4,4a,5,6,9,10,11,12,12a,12bdodecahydro-11-hydroxy-4,6-dimethoxy-4a,8,13,13-
`tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester,(α R, β S)-
`
`
` A
`
`
`Molecular formula: C45H57NO14 . C3H6O
`
`
`
`
`

`

`Molecular weight: 894.01 (for the acetone solvate); 835.93 (for the non solvated form)
`
`ACTION LETTER NOTE: The approved drug substance retest interval to be
`conveyed to the sponsor is
`
`
`Drug Product.
`
`The drug product is supplied as a non aqueous solution (60 mg cabazitaxel in 1.5mL
`polysorbate-80) and a co-packaged diluent (13% Ethanol in WFI).
`
`The diluent vial contents are added to the drug containing vial (both are glass vials with
`rubber stoppers) and mixed gently (to avoid precipitation). This pre-mix solution is
`supersaturated by about 400% and is inherently physically unstable. It is labeled to be
`used immediately. The applicant has not adequately characterized the nucleation and
`kinetics of precipitation (which is known to occur). The in-use handling of the pre-mix
`has not been adequately supported by data.
`
`ACTION LETTER NOTE: A post marketing requirement (PMR) is to be conveyed
`to the applicant to resolve this pre-mix issue within six months of approval
`
`The pre-mix solution is added to the infusion vehicle (NS or D5W) which is also
`supersaturated, also by about 400%. This infusion solution has not adequately
`characterized regarding the nucleation and kinetics of cabazitaxel precipitation (which is
`known to occur). The in-use handling and storage of the infusion solution (24 hours
`refrigerated, 8 hours room temperature) has not been adequately supported by data.
`
`ACTION LETTER NOTE: A post marketing requirement (PMR) is to be conveyed
`to the applicant to resolve this infusion solution issue within six months of approval
`
`Given the important therapeutic nature of this drug product, and the fact that patients
`survive longer when given this drug; these drug product deficiencies may be managed
`post approval within six months as PMRs.
`
`The drug product is to be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59°
`to 86°F) Do not refrigerate.. An 18-month expiry period is recommended to be approved.
`
`Rik Lostritto, Director, ONDQA Division I
`
`(b) (4)
`
`

`

`Application
`Type/Number
`--------------------
`NDA-201023
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SANOFI AVENTIS
`SPA
`
`------------------------------------------
`CABAZITAXEL (XRP6258)
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD T LOSTRITTO
`06/08/2010
`
`

`

`
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`
`
`CHEMISTRY REVIEW
`
`NDA 201-023
`
`JEVTANA (cabazitaxel) Injection
`
`Sanofi-aventis U.S. Inc.
`
`
`
`Xiao-Hong Chen, Ph.D.
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`
`CMC Review of NDA 201-023
`
`For the Division of Drug Oncology Products (HFD-150)
`
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`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`
`
`Table of Contents .......................................................................................................................... 2
`
`Chemistry Review Data Sheet...................................................................................................... 4
`Molecular formula: C45H57NO14 . C3H6O......................................................................... 6
`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 Chemistry Assessment ..........................................................................................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.......................................... 12
`C. Basis for Approvability or Not-Approval Recommendation ............................................ 13
`
`III. Administrative.........................................................................................................................13
`A. Reviewer’s Signature ........................................................................................................ 13
`See appended electronic signature page. ................................................................................ 13
`B. Endorsement Block ........................................................................................................... 13
`C. CC Block........................................................................................................................... 13
`
`Chemistry Assessment................................................................................................................ 14
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.......14
`S DRUG SUBSTANCE [Cabazitaxel] ................................................................................... 14
`S.1 General Information [Cabazitaxel]............................................................................ 14
`S.2 Manufacture [Cabazitaxel]........................................................................................ 16
`S.3 Characterization [Cabazitaxel].................................................................................. 20
`S.4 Control of Drug Substance [Cabazitaxel] ................................................................. 30
`S.5 Reference Standards or Materials [Cabazitaxel]....................................................... 56
`S.6 Container Closure System [Cabazitaxel] .................................................................. 58
`S.7 Stability [Cabazitaxel]............................................................................................... 58
`
`
`
`P DRUG PRODUCT [Cabazitaxel Injection]......................................................................... 62
`P.1 Description and Composition of the Drug Product [Cabazitaxel Injection] ............. 62
`
`Page 2
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`CHEMISTRY REVIEW
`
`
`
`P.2 Pharmaceutical Development [Cabazitaxel Injection].............................................. 63
`P.3 Manufacture [Cabazitaxel Injection]......................................................................... 77
`P.4 Control of Excipients [Cabazitaxel Injection]........................................................... 84
`P.5 Control of Drug Product [Cabazitaxel Injection]...................................................... 86
`P.6 Reference Standards or Materials [Cabazitaxel Injection]...................................... 103
`P.7 Container Closure System [Cabazitaxel Injection] ................................................. 103
`P.8 Stability [Cabazitaxel Injection].............................................................................. 106
`
`P DRUG PRODUCT [Cabazitaxel Solvent for Dilution]..................................................... 111
`P.1 Description and Composition of the Drug Product [Cabazitaxel Solvent for Dilution]
`....................................................................................................................................... 111
`P.2 Pharmaceutical Development [Cabazitaxel Solvent for Dilution].......................... 112
`P.3 Manufacture [Cabazitaxel Solvent for Dilution]..................................................... 114
`P.4 Control of Excipients [Cabazitaxel Solvent for Dilution]....................................... 118
`P.5 Control of Drug Product [Cabazitaxel Solvent for Dilution].................................. 119
`P.6 Reference Standards or Materials [Cabazitaxel Solvent for Dilution].................... 126
`P.7 Container Closure System [Cabazitaxel Solvent for Dilution] ............................... 127
`P.8 Stability [Cabazitaxel Solvent for Dilution]............................................................ 127
`A APPENDICES .................................................................................................................. 132
`R REGIONAL INFORMATION ......................................................................................... 132
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1..................................132
`A. Labeling & Package Insert............................................................................................... 132
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................... 139
`
`
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`Page 3
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`

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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`Chemistry Review Data Sheet
`
`
`
`
`1. NDA 201-023
`
`
`2. REVIEW #1
`
`
`3. REVIEW DATE: 02-June-2010
`
`
`4. REVIEWERS: Xiao-Hong Chen, Ph.D.
`
`
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`
`IND 56,999
`
`
`
`
`
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Document Date
`
`21-MAY-2001
`
`Document Date
`25-FEB-2010
`12-MAR-2010
`17-MAR-2010
`16-APR-2010
`07-MAY-2010
`21-MAY-2010
`25-MAY-2010
`28-MAY-2010
`
`
`Submission(s) Reviewed
`Original
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`Name: Sanofi-Aventis U.S. Inc.
`on behalf of sanofi-aventis U.S. LLC
`
`Page 4
`
`

`

`
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`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Address: 55 Corporate Drive
`Bridgewater, NJ 08807
`Representative: Linda Gustavson, PhD, RAC
`
`Telephone: 610-889-8246
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: N/A
`b) Non-Proprietary Name (USAN): Cabazitaxel (USAN: application pending)
`Code Name/# (ONDQA only): RPR116258A (RPR116258, acetone solvate), XRP6258
`Chem. Type/Submission Priority (ONDQA only):
`• Chem. Type: 1
`• Submission Priority: P
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`
`10. PHARMACOL. CATEGORY: Metastatic prostate cancer that progressed on
`or after docetaxel-based treatment
`
` Concentrate for solution for infusion
`
`
`11. DOSAGE FORM:
`
`
`12. STRENGTH/POTENCY: 60 mg/1.5 mL
`
`
`
`13. ROUTE OF ADMINISTRATION: Intravenous
`
`
`14. Rx/OTC DISPENSED: _X_Rx ___OTC
`
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`
`
` SPOTS product – Form Completed
`
` X Not a SPOTS product
`
`
`
`
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`Page 5
`
`

`

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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`benzenepropanoic acid, β -[[(1,1-dimethylethoxy)carbonyl]amino]-α -hydroxy-,
`(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-(acetyloxy)-12-(benzoyloxy)-
`2a,3,4,4a,5,6,9,10,11,12,12a,12bdodecahydro-11-hydroxy-4,6-dimethoxy-4a,8,13,13-
`tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester,(α R, β S)-
`
`
`
`
`
`Molecular formula: C45H57NO14 . C3H6O
`
`Molecular weight: 894.01 (for the acetone solvate); 835.93 (for the solvent free)
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`A. Supporting DMFs:
`
`
`DMF # TYPE
`II
`
`II
`
`II
`
`II
`
`II
`
`III
`
`III
`
`III
`
`III
`
`HOLDER
`Sanofi Chimie
`
`Sanofi Chimie
`
`ITEM
`REFERENCED
`XRP6258
`cabazitaxel
`acetone solvate
`
`CODE1
`1
`
`STATUS2 DATE REVIEW
`COMPLETED
`Adequate
`06/02/2010
`
`1
`
`3
`
`Adequate
`
`06/02/2010
`
`Adequate
`
`10/28/2008
`
`N/A
`
`N/A
`
`N/A
`
`Adequate
`
`06/02/2010
`
`N/A
`
`N/A
`
`N/A
`
`Adequate
`
`Adequate
`
`Adequate
`
`Date of this
`review
`
`Date of this
`review
`Date of this
`review
`5/20/10
`
`4/12/07
`
`3/23/07
`
`1
`
`4
`
`4
`
`4
`
`1
`
`3
`
`3
`
`Page 6
`
`COMMENTS3
`Reviewed by Brian
`Rogers
`
`Reviewed by Brian
`Rogers
`Reviewed by by Chengyi
`Liang
`Withdrawn from the
`application.
`Reviewed by Brian
`Rogers
`See section 3.2.P.7
`
`See section 3.2.P.7
`
`See section 3.2.P.7
`
`Reviewed by Sue-Ching
`Lin
`
`Reviewed by Mark
`Sassaman
`
`Reviewed by Mark
`Sassaman*
`
`(b) (4)
`
`(b) (
`
`(b) (4)
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`*There was a typographical error in the spelling of
`
`
`-
`
` in the 3/23/07 review. It was incorrectly spelled as
`
`
`
`1 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")
`
` 2
`
` Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`3 Include reference to location in most recent CMC review
`
`B. Other Supporting Documents:
`
`Doc #
`
`OWNER
`
`
`
`
`
`
`
`
`
`ITEM
`REFERENCED
`
`DATE REVIEW
`COMPLETED
`
`STATUS
`
`
`
`
`
`
`
`
`
`
`
`
`COMMENTS
`
`
`C. Related Documents:
`
`
`
`
`
`
`
`
`
`
`
`
`DOCUMENT
`
`OWNER
`
`DESCRIPTION/COMMENT
`
`
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`
`
`CONSULTS
`
`SUBJECT
`
`
`EES
`Pharm/Tox
`
`
`Site inspections
`DS and DP Impurity
`
`DATE
`FORWARD
`ED
`
`8-APR-2010
`20-NOV-2009
`
`STATUS/
`REVIEWE
`R
`
`Acceptable
`Acceptable
`
`Biopharm
`ODS/DMEPA
`
`N/A
`Labeling consult
`
`
`
`
`Methods Validation
`EA
`
`N/A
`N/A
`
`Date of this review
`Date of this review
`
`
`Acceptable for trade
`name
`Pending for
`container labels
`Acceptable
`Acceptable
`
`Page 7
`
`COMMENTS
`
`
`OC recommendation received on 3-MAY-2010
`Consult through email. Refer to Dr. Sachia
`Khasar’s emails attached at the end of this
`review.
`
`Pending
`
`
`Dr. Raanan Bloom in OPS concluded in his
`
`APPLICATI
`ON
`NUMBER
`56,999
`20449
`
`IND
`NDA
`
`Sanofi
`Sanofi
`
`
`
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Sterility assurance
`
`
`
`Acceptable
`
`5/4/10 e-mail that the EA categorical exclusion
`claim, as submitted in the 4/16/10 amendment,
`is appropriate.
`
`
`
`
`
`
`
`Microbiology
`
`
`
`Page 8
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`

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`CHEMISTRY REVIEW
`Executive Summary Section
`The Chemistry Review for NDA 201-023
`
`The Executive Summary
`
` I. Recommendations
`
`
`
`
`
`
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is approvable from a chemistry, manufacturing, and controls
`(CMC) standpoint pending an “acceptable” recommendation from the
`microbiology review. The Office of Compliance has issued an overall
`“acceptable” recommendation for the application. The following comments
`should be included in the NDA action letter:
`
`1. Based on the 12 months primary stability data, 6 month of accelerated data, and
`36 months of the supportive stability data for drug substance and per ICH Q1E
` with storage at 5oC can be granted.
`guidelines, an initial retest date of
`
`2. Based on the 12 months primary stability data, 6 month of accelerated data for
`drug product and diluent, and per ICH Q1E guidelines, an initial expiration
`dating period of 18-months for the drug product stored under the following
`conditions can be granted:
`
`
`
`
`
`
`
`
`II.
`
`- Store at 25°C (77°F); excursion permitted between 15°C – 30°C (59°F – 86°F)
`- Do not refrigerate.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`
`
`Refer to the CMC PMRs to be conveyed to the applicant on June 2, 2010.
`
`Summary of Chemistry Assessment
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`
`Cabazitaxel in combination with prednisone or prednisolone is indicated for the treatment of
`patients with hormone refractory metastatic prostate cancer previously treated with a docetaxel-
`containing regimen. The recommended dose of cabazitaxel is 25 mg/m2 administered as a 1-hour
`intravenous infusion every 3 weeks, in combination with oral prednisone 10 mg administered
`daily throughout cabazitaxel treatment.
`
`Drug Substance
`Cabazitaxel (also referred as RPR116258 / XRP6258) is an antineoplastic agent belonging to the
`taxane class.
`
`
`Page 9
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`(b) (4)
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`

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`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
` Cabazitaxel acetone
` powder which is practically insoluble in water
` freely
`solvate is a
`soluble in acetone and dichloromethane; and soluble in ethanol. Due to its extreme low solubility
`in aqueous solution, the cabazitaxel drug product is formulated in
` polysorbate 80.
`
`
` and
` The DMFs were reviewed by Dr. Brian Rogers. DMFs
` was
` have resolved their deficiencies and are adequate to support the NDA. DMF
`reviewed previously by Chengyi Liang and found to be adequate to support a supplemental
`NDA. Clinical batches of drug substance were manufactured at Vitry France, which is also the
`same site used to manufacture the three primary stability batches and will be the commercial
`drug substance supplier.
`
`Batch release data for the toxicology batches, early clinical batches, late clinical batches, primary
`stability batches and production batches were submitted. All tests conform to their criteria.
`During development, the following analytical methods were revised - HPLC for assay and
`related substances, GC for residual solvents, and microbial contamination test. Submitted data
`for the HPLC methods demonstrate that the updated HPLC method is comparable to the old
`HPLC method.
`
`Controls for release and stability include testing for appearance, identification, assay, pH, color
`and clarity of the solution, purity, individual and total related substances, acetone content,
`residual solvents,
` heavy metals, water content and bacterial endotoxins. Organic
`impurities have either been qualified by toxicology studies or limited to the ICH Q3A
`recommended qualification threshold. Residual solvents are also controlled according to ICH
`Q3C guidelines except for acetone which is part of the solvate. Qualification of the specified
`impurities was consulted to the pharm/tox reviewer, , Dr. Sachia Khasar. With a few exceptions,
`
`Page 10
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`(b) (4)
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`
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`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`
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`
`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
`
`the applicant’s claimed qualification levels have been found acceptable (refer to Dr. Khasar’s
`emails attached at end of this review).
`
` A
`
`, was identified in the Ames test. Test results for
` genotoxic impurity,
`
`
` in the 3 primary stability batches and the 3 production batches show less than
`Safety evaluation of the observed levels of
` in the drug substance batches has been
`consulted to the pharm/tox reviewer. Based on Dr. Khasar‘s assessment, up to
` of
` in the drug substance is acceptable considering the patient population.
`
`
`Stability studies were conducted at both long term (5ºC) and accelerated (25ºC/60% RH) storage
`conditions. Twelve months of long term and 6 months accelerated stability data from the 3
`primary stability batches manufactured at the production scale using a process that is
`representative of the commercial process were submitted. All tests are within the proposed
`criteria. Overall, the drug substance appears to be stable under both long term and accelerated
`storage conditions. Photostability studies and other stress studies were conducted to characterize
`physical and chemical stability. Results show that drug substance is slightly photosensitive when
`exposed to intense light. Based on the available stability data and per ICH Q1E guidelines, an
`
` retest period for the drug substance stored under the refrigerated conditions (2–8oC) can
`be granted.
`
`Drug Product
`The drug product, JEVTANA (cabazitaxel) Injection, 60 mg/1.5 mL, is supplied as a non-
`aqueous concentrated solution for infusion co-packaged with a diluent vial containing 5.7 mL of
`a 13% w/w aqueous solution of alcohol (USP). The diluent is to be used for preparation of a
`premix solution of 10 mg/mL of cabazitaxel, followed by a second dilution of the appropriate
`dose in 0.9% sodium chloride solution or 5% dextrose solution in an infusion bag. Both
`concentrated drug solution and the diluent are each packaged in a 15 mL Type I clear glass vial
`closed with a grey
` rubber closure with a transparent
`
` and capped with an aluminum cap covered with a light green plastic flip-off cap.
`All formulation excipients comply with USP/NF compendial requirements.
`
` of cabazitaxel acetone solvate in aqueous solution
`Due to the
`the drug product is formulated with a
`polysorbate 80. The overall drug product
`manufacturing process and formulation was unchanged during drug development and through
`commercialization. The commercial and clinical formulations differ in fill volume of the vials;
`80 mg/2 mL for the clinical formulation and 60 mg/1.5 mL for the commercial formulation.
`Drug product is manufactured by Aventis Pharma in Dagenham, United Kingdom. The proposed
`commercial batch size is
` which will produce approximately
`
` The drug product manufacturing process is
`
`
`
`
`
`
`
`
`
`
`
`
`In-use compatibility studies for the premix solution and infusion solution demonstrate suitable
`chemical stability of both solutions when stored under the ambient or refrigerated conditions.
`
`
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`Page 11
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b)
`(4)
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`(b) (4)
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`

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`
`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
`
`Physical stability studies have demonstrated that both the premix solution and the infusion
`solution are
` which have a risk of crystallization when stored
`extensively, i.e. crystallization was observed in infusion solution stored at 30oC for 48 hours. The
`instruction in the package insert for the preparation and storage of the premix solution and the
`infusion solution includes cautionary statement and directions to avoid the potential
`crystallization situations. In addition, a proposed post-marketing requirement to study the
`physical stability has been conveyed to the applicant.
`
`The drug product specification is typical for a small parenteral product for IV administration and
`includes testing for appearance, identification, pH, assay, degradation products, particulate
`matter, bacterial endotoxins, and sterility. Degradation products are limited to the ICH Q3B
`recommended qualification threshold and/or the maximum qualification levels of the toxicology
`studies (acceptance with concurrence of the pharm/tox reviewer, Dr. Khasar).
`
`Primary stability studies were conducted at both long term (5ºC, 25ºC/60%RH, and
`30ºC/65%RH) and accelerated (40ºC/75%RH) storage conditions on 3 registration batches
`manufactured at the intended commercial scale and site using the proposed commercial process,
`and packaged in the proposed commercial packaging system. Twelve months of long term (each
`condition) and 6 months of accelerated primary stability data are submitted. Based on the
`primary stability data generated on three commercial scale batches stored under the long term
`storage conditions (25°C/60% RH and 30°C/65 % RH) and per ICH Q1E guidelines, an 18
`months shelf life can be grated. Long term stability data on the diluent vials also supports an
`initial 18 month shelf life. Since the drug product configuration is a two vial kit, the overall shelf
`lif