CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-372
`
`Chemistry Review(s)
`
`

`

`NDA 21-372
`
`Aloxi (palonosetron HCl) Injection 25 mg/5 mL
`
`CHEMISTRY DIVISION DIRECTOR REVIEW
`
`Applicant:
`
`Helsinn Healthcare S.A.
`
`Indication:
`
`Prevention of accute and delayed nausea and vomiting associated with
`initial and repeated courses of emetogenic cancer therapy
`
`Presentation: 25 mg/SmL -\
`
`EER Status: Acceptable l4-JUL-2003
`
`Consults:
`
`ODS — Tradename: Aloxi- acceptable 9-JAN-2003
`Statistics — none
`
`EA — no consult - waiver requested — granted
`
`CMC Phase IV Commitments: none
`
`The original NDA was received 26-SEP-2002
`
`The drug substance is manufactured by:
`
`Helsinn Advanced Synthesis
`Biasca, SZ
`
`DMF 16,063
`
`\,
`
`from well characterized commercially available starting
`The synthetic process is —-‘
`materials. The manufacturing process is well defined and in-process controls are
`adequate.
`
`Structural characterization of the drug substance was satisfactory. Specifications were
`found acceptable. Impurities and degradation products were well studied and are
`adequately controlled. A re-test period of 12 months is supported by submitted stability
`data — the applicant had requested a ’— re-testperiod. The stability testing
`protocol is considered adequate.
`
`Conclusion
`
`Drug substance is acceptable.
`
`

`

`The drug product is formulated as an aqueous solution with mannitol, buffering agents
`with pH adjustment
`25 mg/5 mL.
`
`Manufacturer:
`
`SP Pharmaceutical
`
`Albuqueque, NM
`
`The manufacturing method is a standard process for a parenteral product with '
`sterilization. The proposed regulatory specifications are acceptable including impurities.
`The proposed W expiry is not supported with suffucient data — the 18 months of
`data provided support a 24 month expiry. The stability testing protocol is considered
`adequate.
`
`
`
`The overall Compliance recommendation is acceptable as of l4-IUL-20003
`
`All associated DMFs are acceptable.
`
`Conclusion
`
`Drug product is acceptable
`
`Overall Conclusion
`
`From a CMC perspective the application should be approved.
`
`Eric P Duffy, PhD
`Director, DNDC Il/ONDC
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Eric Duffy
`7/18/03 11:43:39 AM
`CHEMIST
`
`

`

`

`

`MEMO
`
`To:
`
`NDA 21-372 (Palonosetron Injection)
`
`From:
`
`Marie Kowblansky, PhD
`
`Through: Ali Al-Hakim, PhD, Acting Team Leader HFD-180
`
`Brian Strongin, Project Manager, HFD-180
`
`Date:
`
`6/30/03
`
`Subject:
`
`Immediate Container and Carton Labeling
`
`The submission from August Consulting (sponsor: Helsinn Healthcare SA), dated June 25, 2003,
`provides FAXed copies of the immediate container and carton labels for the above product.
`
`Drug vial:
`the amount of
`injecton,
`The label gives the product name, AloxiTM palonosetron HCI
`palonosetron per milliliter and per 5 milliliters, a statement that the product is for intravenous
`single-use,
`lot number, expiration date, and the distributor's name.
`The applicant was
`contacted by telephone on June 30th with the request that the storage conditions be added to
`the label. The applicant agreed with our request. However,
`in view of the small size of the
`label,
`the phrase N " will be deleted from the label, and the storage
`
`statement will read “protect from light" and “Store at 20°C-25°C (60°F-77°F)", omitting the
`phrase ‘
`In view of the limited space on the label and the
`fact
`that all
`the omitted statements are included on the carton label,
`this is considered
`acceptable.
`
`CARTON LABEL
`
`The carton label contains the same information as on the drug vial, the complete storage
`statement,
`lot number, expiration date, and the full composition of the dmg product, and
`identifies the distributor. This is considered acceptable.
`
`_
`SHIPPER CARTON LABEL (2-1-127)
`The carton label contains the product name, concentration of the active in the product, lot
`number, expiration date, complete storage statement and manufacturer and distributor. The
`box also indicates the number of single-use vials that are found in the box.
`This is
`considered acceptable.
`
`In a July 15' FAX, the applicant confirms the agreements described above from the June 30"1
`teleconference.
`
`v'\.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Marie Kowblansky
`7/1/03 10:52:40 AM
`CHEMIST
`
`Ali Al-Hakim
`
`7/1/03 10:57:26 AM
`CHEMIST
`
`.¢1n~\_
`
`

`

`CHEMISTRY REVIEW
`
`NDA 21-372
`
`Palonosetron Hydrochloride
`Intravenous Injection, 0.25 mg
`(0.05 mg/mL)
`
`Helsinn Healthcare SA
`
`Marie Kowblansky, Ph.D.
`DIVISION OF GASTROINTESTINAL AND COAGULATION
`
`‘ DRUG PRODUCTS
`
`

`

`CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents
`
`............. 2
`
`Chemistry Review Data Sheet ............................................. 4
`
`The Executive Summary ......................................................................................... 7
`
`1. Recommendations ....................................................................................................................... 7
`
`A. From the chemistry perspective, this application is Approvable, pending ....................................... 7
`
`1. Resolution of the issues cited in the Draft Deficiency letter, the most notable of which is a
`tightening of impurity specifications to reflect the actual manufacturing history and levels found
`in supplies used in clinical trials. The deficiencies have been communicated to the applicant.
`Error! Bookmark not defined.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable — No post-approval conunitments are required at the present
`time ................................................................................................................................................... 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
`
`At this time, this application is judged to be Approvable based on the issues cited above (under
`Recommendations) ........................................................................................................................... 8
`
`III. Administrative .......................................................................................................................... 8
`
`A. Reviewer’s Sig-nature ........................................................................................................................ 8
`
`B. Endorsement Block ........................................................................................................................... 8
`
`C. CC Block .......................................................................................................................................... 8
`
`Chemistry Assessment ............................................................................................ 9
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ...... 12
`
`' S DRUG SUBSTANCE [palonosetron hydrochloride, Helsinn] ................................ see Review #1
`
`P DRUG PRODUCT [palonosetron hydrochloride Injection] .................................... see Review #1
`
`A APPENDICES ....................................................................... ..................................... see Review #1
`
`R REGIONAL INFORMATION ....... C ......................................................................... see Review #1
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1Error! Bookmark not defined.
`
`

`

` CHEMISTRY REVIEW
`
`A. Labeling & Package lnsen ......................................................................................... see Review #1
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ............................... see Review #1
`
`11]. List Of Deficiencies To Be Communicated ................................................. '. ...................... none
`
`APPEARS nus my
`ON OR!G l HAL
`
`APPEARS THIS WAY
`0N ORlGlNAL
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA21-372'
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: May 23, 2003
`
`4. REVIEWER: Marie Kowblansky, PhD.
`
`a
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`None -
`
`_
`
`'
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`Submission 5 Reviewed
`
`Original
`BC
`BC
`BC
`BC
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`September 26, 2003
`November 21, 2003
`April 9, 2003
`June 13, 2003
`June 20, 2003
`
`Name:
`
`Helsinn Healthcare SA
`
`Via Pian Scairolo
`
`Address:
`
`6912 Pazzallo (Lugano)
`Switzerland
`
`Representative:
`
`Craig Lehmann, PharmD.
`
`Telephone:
`Fax:
`
`(512) 347-1755
`15121347-9375
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: (3a§)—2-[(§)-l-Azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-l-oxo-1fl-
`benz[de]isoquinoline hydrochloride
`
`b) Non-Proprietary Name (USAN): palonosetron hydrochloride
`c) Code Name/# (ONDCS only): NA
`d) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type:
`
`1
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`Page 4 of 12
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`10. PHARMACOL. CATEGORY: antiemetic and antinauseant
`
`ll. DOSAGE FORM: sterile solution
`
`12. STRENGTH/POTENCY: 0.05 mg/mL; 0.25 mg/via]
`
`I3. ROUTE OF ADMINISTRATION:
`
`intravenous injection
`
`14. Rx/OTC DISPENSED:
`
`\/ Rx
`
`OTC
`
`15. SPOTS SPECIAL PRODUCTS ON-LINE TRACKING SYSTER N0te26 :
`
`SPOTS product — Fom) Completed
`
`\/ Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORIVIULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`CHEMICAL NAME:
`
`(3a§)—2-[(§)-l -Azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-ox0-
`lfl-benz[de]isoquinoline hydrochloride
`
`0
`
`N “III
`
`,
`
`’n
`
`.llt‘l
`
`MOLECULAR FORMULA:
`MOLECULAR WEIGHT:
`
`C19H24NZO.HCI
`332.87
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DMF #
`
`HOLDER
`Helsinn Advanced
`
`
`
`-
`
`
`
`Synthesis
`'_16063
`Action codes for DMF Table:
`l — DMF Reviewed.
`
`ITEM
`REFERENCED CODE
`
`1
`
`
`2 DATE REVIEW
`STATUS COMPLETED
`
`Drug substance
`
`Adequate
`
`June 24, 2003
`
`OMMENT
`
`
`
`
`
`‘
`
`
`
`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)
`'
`
`Page 5 of 12
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`B. Other Documents:
`
`APPLIC ION NUMBER
`DOCUMENT
`_—.. _
`
`DESCRIPTION
`
`18. STATUS:
`
`CONSULTS/ CMC
`
`
`
`
`_——m_—
`
`
`——-——
`
`-_—5___
`
`——_—_
`
`_—m-——
`
`
`
`
`
`
`1. Way
`*The applicant appropriately claims categorical exclusion on the basis that the concentration of the active moiety will
`not exceed 1 ppb at the point of entry into the aquatic environment.
`
`
`
`APPEARS nus wm
`0N ORIGINAL
`
`Page 6 of 12
`
`

`

` CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`The Chemistry Review for NDA 21-372
`
`The Executive Summam’
`
`1. Recommendations
`
`A. From the chemistry perspective, this application may be Approved pending
`
`l. completion ofa satisfactory GMP inspection. (Inspection scheduled to begin June 26”)
`
`
`2. a written decision by the toxicology reviewer that
`
`are qualified to be
`and
`the relatively high levels of ‘- 3, as proposed by the applicant.
`(In a
`present at
`palonosetron team meeting held June 24, 2003, Dr. Y Chopra indicated that
`the
`Phannfl'ox. Review will indicate that the proposed levels are considered toxicologically
`qualified.)
`
`impurities
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable — None required
`
`11. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`is synthesized as the (5,8)-
`It
`The active drug substance is palonosetron hydrochloride.
`stereoisomer and contains two chiral centers, with four potential stereoisomers or two
`diastereomeric pairs of enantiomers. The enantiomeric purity of the final product is assured by
`control over the enantiomeric purity of the starting material and of the intermediates. No
`
`racemization has been observed (by
`\ at either of the two stereocenters, either
`under synthetic conditions or under stressed stability testing.
`
`The applicant proposes
`_
`
`relatively high specification limits of ~ '6 for two of the impurities
`
`,
`.
`_
`..
`_ -
`_
`. At these levels, they will
`have to be toxicologically qualified per ICH Guidelines. Consequently, the acceptability of
`these specification limits will be decided when the toxicology review has been completed.
`
`. sterilized buffered solution for IV administration. It
`'
`The proposed drug product is a ..
`is supplied in 5 mL vials containing 0.25 mg palonosetron (as the hydrochloride), mannitol,
`disodium edetate, and citrate buffer in water for injection. Sodium hydroxide or hydrochloric
`acid are used for adjustment to pH 5. It is packaged in "’
`_ glass single—dose vials. The
`product. has been found to be unstable when exposed to light. Consequently,
`the vial
`is
`packaged in an outer carton, which serves to protect it from light, resulting in a stable product.
`Based on the 18-month primary stability data that were submitted for product manufactured at
`the current manufacturing site, a 24 month expiration is appropriate for the product at the
`present time.
`
`Page 7 of 12
`
`

`

`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`
`The applicant makes repeated references to higher concentration formulations,
`NOTE:
`particularly . - mg/mL, and provides data for these formulations. Since this NDA is for a
`single product that contains 0.05 mg/mL ofpalonosetron, the information regarding the higher
`dose formulations has not been carefully reviewed, but was used as supporting information,
`when warranted.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The dosing instructions call for infusing intravenously over 10 to 30 seconds.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`At this time, this application is judged to be Approvable from the CMC perspective, pending
`resolution of the issue cited above (under Recommendations).
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Chemistry Reviewer: Marie Kowblansky, Ph.D.
`ChemistryTeamLeader: Liang Zhou, Ph.D.
`ProjectManager: Brian Strongin
`
`C. CC Block
`
`,..Jfi~\‘
`
`Page 8 of 12
`
`

`

`

`

`-----------------------—--~---------------------"------------------------------------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Marie Kowblansky
`6/24/03 04:39:09 PM
`CHEMIST
`
`Liang Zhou
`6/24/03 05:03:27 PM
`CHEMIST
`
`Pending EER.
`
`

`

` CHEMISTRY REVIEW
`
`NDA 21-372
`
`Palonosetron Hydrochloride
`Intravenous Injection, 0.25 mg
`(0.05 mg/mL)
`
`Helsinn Healtheare SA
`
`Marie Kowblansky, Ph.D.
`DIVISION OF GASTROINTESTINAL AND COAGULATION
`
`DRUG PRODUCTS
`
`

`

`CHENIISTRY REVIEW
`
`Table of Contents
`
`Table of Contents .................................................................................................. 2
`
`Chemistry Review Data Sheet ................................................................................ 4
`
`The Executive Summary ......................................................................................... 7
`
`1. Recommendations ........................................................................................................................ 7
`
`A. From the chemistry perspective, this application is Approvable, pending ....................................... 7
`1. Resolution ofthe issues cited in the Draft Deficiency letter, the most notable ofwhich is a
`tightening of impurity specifications to reflect the actual manufacturing history and levels found
`in supplies used in clinical trials. The deficiencies have been communicated to the applicant. ..... 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable — No post-approval commitments are required at the present
`‘ time ................................................................................................................................................... 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
`
`At this time, this application is judged to be Approvable based on the issues cited above (under
`Recommendations) ........................................................................................................................... 8
`
`III. Administrative .......................................................................................................................... 8
`
`A. Reviewer’s Signature ........................................................................................................................ 8
`
`B. Endorsement Block ........................................................................................................................... 8
`
`C. CC Block .......................................................................................................................................... 8
`
`Chemistry Assessment ............................................................................................ 9
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ........ 9
`
`S DRUG SUBSTANCE [palonoseU’on hydrochloride, Helsinn] ...................................................... 9
`
`P DRUG PRODUCT [palonosetron hydrochloride Injection] ........................................................ 12
`
`A APPENDICES ............................................................................................................................... 26
`
`R REGIONAL INFORMATION ..................................................................................................... 26
`
`H. Review Of'Common Technical Document-Quality (Ctd-Q) Module 1 .................................. 27
`
`A. Labeling & Package Insert ............................................................................................................. 27
`
`

`

` CHEMISTRY REVIEW
`
`B. Enviromnemal Assessment Or Claim Of Categorical Exclusion ................................................... 28
`
`III. List Of Deficiencies To Be Communicated ............................................................................ 28
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NBA 21-372
`
`2. REVIEW_#:1
`
`3. REVIEW DATE: May 23,2003
`
`4. REVIEWER: Marie Kowblansky,Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`None
`
`6. SUBMISSION(S) BEING REVIEWED:
`Submission 5 Reviewed
`
`Original
`BC
`
`BC
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`Document Date
`
`September 26, 2003
`November 21, 2003
`
`April 9, 2003
`
`Name:
`
`Helsinn Healthcare SA
`
`Via Pian Scairolo
`
`Address:
`
`6912 Pazzallo (Lugano)
`Switzerland
`
`Representative:
`
`Craig Lehmann, PharmD.
`
`Telephone:
`
`(512) 347-1755
`
`Fax:
`
`15121347-9375
`
`8. DRUG PRODUCT NAME/CODE/I‘YPE:
`
`a) Proprietary Name: (3a_S_)-2-[(§)-1-Azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-l-oxo-1fl-
`benz[de]isoquinoline hydrochloride
`
`b) Non-Proprietary Name (USAN): palonosetron' hydrochloride
`c) Code Name/# (ONDCS only): NA
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type:
`
`1
`
`0 Submission Priority: S
`
`Page 4 on9
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`10. PHARMACOL. CATEGORY: antiemetic and antinauseant
`
`ll. DOSAGE FORM: sterile solution
`
`12. STRENGTH/POTENCY: 0.05 mg/mL; 0.25 mg/vial
`
`l3. ROUTE OF ADMINISTRATION:
`
`intravenous injection
`
`14. Rx/OTC DISPENSED:
`
`\/ Rx
`
`OTC
`
`15. SPOTS SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM Note26 :
`
`SPOTS product — Form Completed
`
`\/ Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`CHEMICAL NAME:
`
`(3a§)—2-[(§)-1-Azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydr0-l-oxo-
`l}_-l-benz[de]isoquinoline hydrochloride
`
`
`
`MOLECULAR FORMULA:
`MOLECULAR WEIGHT:
`
`C19H24N20.HC1
`332.87
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
`HOLDER
`Helsinn Advanced
`
`Synthesis
`16063
`Action codes for DMF Table:
`l —- DMF Reviewed.
`
`ITEM
`REFERENCED CODE
`
`1
`
`STATUS
`
`2 DATE REVIEW
`COMPLETED
`
`OMMENT
`
`Drug substance
`
`Inadequate March 29, 2003
`
`‘
`
`
`
`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")
`
`Page 5 of 29
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents:
`
`DESCRIPTION
`.o I u MBER
`APPLIC-
`DOCUMENT
`__-——
`
`l8. STATUS:
`
`.
`
`CONSULTS/ CMC
`RELATED REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`‘The applicant appropriately claims categon'cal exclusion on the basis that the concentration ofthe active moiety will
`not exceed 1 ppb at the point of entry into the aquatic environment.
`
`APPEARS rms WA Y
`0H ORIGWAL
`
`.r“\\
`
`Page 6 of 29
`
`

`

`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`The Chemistry Review for NBA 21-372
`
`The Executive Summafl -
`
`1. Recommendations
`
`A. From the chemistry perspective, this application is Approvable, pending
`
`1. Resolution of the issues cited in the Draft Deficiency letter, the most notable of which is a
`tightening of impurity specifications to reflect the actual manufacturing history and levels
`found in supplies used in clinical trials.
`
`2. Resolution of the deficiencies in the drug substance DMT. The deficiencies have already
`been communicated to the DMF holder.
`
`\f—
`3. A decision by the toxicology reviewer that impurities
`and
`K
`, are qualified to be present at the
`relatively high levels proposed by the applicant.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable - No post—approval commitments are required at
`the
`present time.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`is synthesized as the (8,8)-
`It
`The active drug substance is palonosetron hydrochloride.
`stereoisomer and contains 2 chiral centers, with four potential
`stereoisomers or
`two
`diastereomeric pairs of enantiomers. The enantiomeric purity of the final product is assured by
`
`control over the enantiomeric purity of the starting material and of the intermediates- No
`racemization has been observed ‘
`_
`at either of the two stereocenters. either
`under synthetic conditions or under stressed stability testing.
`
`.
`
`The applicant proposes
`
`relatively high specification limits of —3 for two of the impurities
`‘
`.
`
`~
`At these levels, they will
`have to be toxicologically qualified per ICH Guidelines. Consequently, the acceptability of
`these specification limits will be decided when the toxicology review has been completed.
`
`It
`The proposed drug product is a x ' sterilized buffered solution for IV administration.
`is supplied in 5 mL vials containing 0.25 mg palonosetron (as the hydrochloride), mannitol,
`disodium edetate, and citrate buffer in water for injection. Sodium hydroxide or hydrochloric
`acid are used for adjustment to pH 5.
`It is packaged in "'
`glass single-dose vials. The
`product has been found to be unstable when exposed to light. Consequently,
`the vial
`is
`packaged in an outer carton, which serves to protect it from light, resulting in a stable product.
`
`.Ia'“
`
`Page 7 of 29
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`

`

` CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`NOTE:
`
`The applicant makes repeated references to higher concentration formulations,
`particularly \ mg/mL, and provides data for these formulations. Since this NDA is for a
`single product that contains 0.05 mg/mL ofpalonosetron, the information regarding the higher
`dose formulations has not been carefully reviewed, but was used as supporting information,
`when warranted.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The dosing instructions call for infusing intravenously over 10 to 30 seconds.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`At this time, this application is judged to be Approvable based on the issues cited above (under
`Recommendations).
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Chemistry Reviewer: Marie Kowblansky, Ph.D.
`ChemistryTeamLeader: Liang Zhou, PhD.
`ProjectManager: Bn'an Strongin
`
`C. CC Block
`
`Page 8 of 29
`
`

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`page; of trade
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`SeCfét and/or
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`commerCi§l_
`
`infOrmation
`
`

`

`---------------------------pnu------.u-u------.---.----------n-u-nn---------------------------------------_---—----.-
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Marie Kowblansky
`6/3/03 06:59:12 PM
`CHEMIST
`
`Liang Zhou
`6/4/03 05:46:53 PM
`CHEMIST
`”“'
`
`can be set limit to less
`
`"
`
`based on DS specifications in IR
`than “-
`request #1. Other imputies Can be also set
`up low limits according to DS specification in
`IR #2.
`
`

`

`

`

`'. Redacted
`
`l7 _
`
`
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`pages of trade
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`Secrét and/or
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`'confidential
`
`

`

`MEMO
`
`To:
`
`NDA 21-372 (Palonosetron Injection)
`
`From:
`
`MarielKowblansky, PhD
`
`Through: Liang Zhou, PhD, Team Leader HFD-180
`
`Brian Strongin, Project Manager, HFD-180
`
`Date:
`
`7/14/03
`
`Subject:
`
`Office of Compliance Manufacturing Facility Recommendation for NDA 21-372
`
`On July 14, 2003 the Office of Compliance issued a recommendation that all facilities associated with
`the manufacture of Palonosetron Injection, 25mg/mL are Acceptable. Their summary report
`is
`reproduced below:
`
`ESTABLISHMENT EVALUATION REQUEST
`
`SUMMARY REPORT
`
`Application
`
`: NDA
`
`21372/000
`
`Sponsor:
`
`HELSINN EEALTHCARE SA
`
`Org Code
`
`Priority
`
`: 183
`
`: 15
`
`6912
`
`PAZZALLO, LUGANO, 52
`
`Stamp Date
`SMG/SML
`
`: 27-SEP-2002
`
`Brand Name
`
`:
`
`PALONESETRON HCL O.
`
`PDUFA Date
`
`: 27—JUL-2003
`
`Estab. Name:
`
`Action Goal
`SMG/SML
`
`: 25—JUL-2003
`
`Generic Name:
`
`FALONOSETRON HCL O.
`
`District Goal:
`
`26—MAY—2003
`
`Dosage Form:
`
`(INJECTION)
`
`Strength
`
`:
`
`0.05 MG/ML
`
`FDA Contacts:
`1-827-7310
`
`B. STRONGIN
`
`Project Manager
`
`(HEB-180)
`
`1-827—7310
`
`1-827-1251
`
`M. KOWBLANSKY
`
`Review Chemist
`
`(HFD-lSO)
`
`L. znou
`
`Team Leader
`
`tHFD-180)
`
`Overall Recommendation:
`) 301-827—9051
`
`ACCEPTABLE on ld-JUL-2003by S. ADAMS
`
`(HFD—I
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Marie Kowblansky
`7/14/03 01:19:41 PM
`CHEMIST
`
`Liang Zhou
`7/14/03 02:24:35 PM
`CHEMIST'
`
`