CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -9 94
`
`CHEMISTRY REVIEW! S!
`
`_
`
`

`

`Food & Drug Administration
`
`Memorandum
`
`Date :
`
`September 20, 2006
`
`From:
`
`Linda Ng, Ph.D.
`Pharmaceutical Assessment Lead for Ophthalmology
`
`Through: Norman Schmuff, Ph.D.
`'
`Branch Chief, ONDQA Division II
`
`Subject:
`
`(travoprost ophthalmic solution)
`NDA 21— 994, Travatan Z
`0.004%, Alcon Research Ltd.
`
`To:
`
`The File
`
`NDA 21—994, Travatan Z (travoprost ophthalmic solution) 0.004% is
`reviewed by Dr. Suresh 'Pagay, chemistry reviewer.
`He is on travel
`this week after completing chemistry review #2 Amendments were
`received after the DFS sign- off of his review The PDUFA date is
`September 21, 2006.
`
`This memo will complement Dr Pagay’ s review #2 to cover amendment
`N— OOOBL dated September 15 for updated labeling and N.—OOOBC dated
`September 19,2006 for response to the outstanding CMC issues.
`
`NDA 21—994 NOOOBL met all the CMC comments on labeling mentioned
`in Dr. Pagay’s review. Acceptable.
`
`'NDA 21, 994 NOOOBC provides confirmation of agreements made via a
`teléConference call of September 16,
`2006 between Alcon and the
`Agency.
`They agreed to ”WWWWWWM expiry dating period for the
`mr ‘Mas14/;.2..22(Eiwnnngv.
`physician sample and trade products with testing at
`-
`products will have
`-w”W “ W expiry if test passes andmm
`if test fails
`They will develop test and acceptance criteria
`
`
`_ .
`”N‘SsMKI-‘B-uuwv«n.1,
`for
`,mfww~
`in
`the
`excipient
`polyoxyl
`4O
`hydrogenated. castor‘ oil
`(ECO—40)
`specification.
`and.
`in.
`the drug
`product specification.
`For the latter,
`they will discuss with the
`Agency and commit to submit a supplement. Acceptable.
`
`

`

`This is a representation 'of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`-
`---_--——---------_---u---_-----_--__----_-----_-----—.._------—---_------—---—----q-——-q-_--——---------______________
`
`Linda Ng
`_9/20/2006 03:00:28 PM
`CHEMIST
`
`’Stephen Paul Miller
`9/20/2006 03:12:25 PM
`.
`CHEMIST
`I
`Acting ONDQA Branch Chief
`
`Appears This WOV
`On Original
`
`

`

`HEMISTRY REVIE
`
`NDA‘ 21—994
`
`TRAVATAN Z
`
`Travoprost ophthalmic solution, 0.004%
`Alcon Research Ltd.
`
`Shrikant N. Pagay
`Anti-Infective and Ophthalmic Drug Products
`CMC REVIEW # 2
`-
`~
`
`Appears This Way
`On Original
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`
`

`

`
`EMISTRY REVIE!
`
`Table of Contents
`
`Table of Contents
`
`............................................................................................... 2
`
`Chemistry Review Data Sheet....... ........
`
`................... ............4 ~
`
`The Executive Summary ...............L...................................................................;.....9
`
`I. Recommendations ...........................................................,........
`
`.................9
`
`A.Recommendation and Conclusion on Approvability ...................................................
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable .........................................................
`
`II. Summary of Chemistry Assessments ...............................................................................9
`
`A. Description of the Drug Product(s) and Drug Substance(s) .....................................
`
`B. Description of How the Drug Product is Intended to be Used ..................................
`C. Basis for Approvability or Not-Approval Recommendation
`
`III.- Administrative....................'............................................................................................ 11
`
`A. Reviewer’s Signature ..................................................Z.................................................
`
`B. Endorsement Block .......................................................................................................
`
`C. CC Block .........................................................................................................................
`
`Chemistry Assessment
`
`...................’................................................... 12
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of
`Data .......................................................................................................................................
`
`s DRUG SUBSTANCE [Name, Manufacturer]..........,.......................................'....... 12
`
`P DRUG PRODUCT [Name, Dosage form] ...................
`
`15
`
`A APPENDICES ................................
`
`R REGIONAL INFORMATION ................................................................................. 65
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`.
`
`

`

` . EMISTRY REVIé;
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ...........................
`
`
`
`V
`
`A. Labeling & Package Insert
`
`..........................................................................................
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion .............................
`
`III. List Of Deficiencies To Be Communicated ................................................................65
`
`IV.
`
`Appendix (Specifications for Drug Substance, Drug Product, Retest Date and
`Shelf life .................................................................................
`
`72
`
`Appears This Way
`On Original
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`
`

`

`
`HEMISTRY REVIEW ,-
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 219994
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: Review 1:2/27/06 (Review 2: Date 8/28/06)
`
`4. REVIEWER: Shrikant N.‘Pagay
`
`5. PREVIOUS DOCUMENTS:__ .
`
`Previous Documents
`
`None
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissiongs) Reviewed
`Original
`'
`. Amendment
`Amendment
`Amendment
`
`.
`
`'
`
`_
`
`'
`
`.
`
`.
`
`Document Date
`11/18/05 I
`12/14/05
`7/25/06 -
`9/1/06
`
`Appears This Way _
`' On Original
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`
`Page 4 of 73
`
`

`

`
`Chemistry Review Data Sheet
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Alcon, Inc,
`Alcon Research, Ltd.
`Mail Code R7-18
`
`Address:
`
`6201 South Freeway
`Fort Worth, TX 76134—2099
`
`Representative: Angela Kothe
`
`Telephone 817- 551- 4933
`
`8. DRUG PRODUCT NAlVIE/CODE/TYPE:
`
`a). Proprietary Name: TRAVATAN® Z (travoprost ophthalmic solution, 0.004%) (Proposed)
`b). Non—Proprietary Name (USAN): Travoprost (USAN, BAN, JAN)
`0). Code Name/# (ONDC only):
`Company or Laboratory Code
`AL-6221 (Alcon)
`AL06221 (Alcon)
`CPI—4074 (Dow)
`' Other Nonproprietary Name(s): NA
`' Chemical Abstracts Service (CAS) Registry Number .
`157283—68—6
`
`Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 5‘
`
`0 Submission PriorityLS
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b) (1)
`
`10. PHARMACOL. CATEGORY: Ophthalmic / Reduction of pressure in
`'
`glaucoma or ocular pressure.
`
`11. DOSAGE FORM: Sterile Solution
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`
`Page 5 of 73
`
`
`
`«WI-”1V
`
`

`

`
`
`Chemistry Review Data Sheet
`
`12. STRENGTH/POTENCY: 0.004%
`
`13. ROUTE OF ADMINISTRATION: Ophthalmic
`
`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.
`_
`,,
`[HQ-[101(2),ZB(IE,,3R*) 301,50L]]- 7--,[35——Dihydroxy—2- [3—hydroxy-4-[3-
`(trifluoromethyl)phenoxy]— I--butenyl]cyclopentyl]-5-heptenoic acid, 1--methylethylester
`
`(Z)—7—[(1R,2R,3R,SS)-3,5 -D1hydroxy—2—[(IE,3R)—3_-hydroxy—4—[(u,a,a-trifluoro-m-isopropyltolyl)
`oxy]- 1 -butenyl]cycloper1tyl]-5—heptenoate
`'
`
`Molecular Formula: C26H35F3O<s
`° Relative Molecular Mass: 500.55
`
`
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`
`Page 6 of 73
`
`

`

`
`
`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
`DMF
`ITEM
`'
`1
`2
`REVIEW
`COMMENTS
`
`
`TYPE HOLDER REFERENCED CODE# STATUS
`COMPLETED ‘
`9/4/06
`
`
`DATE
`
`
`
`
`
`
`
`
`
`
`
`9/4/06
`
`
`
`9/4/06
`
`
`
`
`
`
` l A — ‘H
`
`
`
`
`
`1 Action codes for DMF Table:
`l — DMF Reviewed.
`
`v
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`V
`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)
`.
`‘
`
` DOCUMENT APPLICATION NUMBER
`
`DESCRIPTION
`
`B. Other Documents:
`
`
`
`Different formulation of the same
`NDA
`21-257
`
`
`
`
`
` drug with preservative.
`
`at???“
`
`
`
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`
`Page 7 of 73
`
`

`

`
`
`Chemistry Review Data Sheet
`
`18. STATUS:
`
`RECOMMENDATION
`
`DATE
`
`RELATED
`REVIEWS
`—_——
`—-_—_
`—_—_
`_—__
`
`REVIEWER
`
`
`
`
`
`
`
`
`
`BAC formulation/ S.Pagay
`negotiated
`——_—
`
`accepted
`
`
`
`19. COMMENTS: Review 2 covers review 1 plus Amendment 9/1/06 : The samples from the 2....
`out of the” lots placed on stability studies and stored forWat W% RH showed
`
` :qufirurp.€>>i€”~7&1‘avfiiltfiémflfi
`particulates identified as thc‘
`_
`with m
`_
`.
`@amwAMVAL’F-‘ft‘flikfim"“ “:zé’waaw‘’35::has?“
`3pm.”); .
`WflMm-flcwmmbw‘thfiP?finez‘é-K-wiéamamkxwymfifimndemama-wwpszgzaww‘i-YEFE‘AmL‘W.‘
`~ MWW.
`
`'8}
`
`
`
`
`
`
`
`Travatan Z samples (drug product) stored up to r---- are free of particulate
`,
`,.
`.,
`nave 10W aqueous solubility Since ‘4,” V e-”
`, pH'of the drug product was decreased from eeefio 5.7. Review 2 covers the
`stabilit u date and r0 osed chan es in the acce tance criteria for H of the dru
`roduct and
`
`label u date. Also settin shelf life fiirther revisions to acka e insert
`label and settin
`
`impurity limits for §”‘
`
`Appears This Way
`On Original
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`
`Page 8 of 73
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 21-994
`
`The Executive Summarl
`
`I. Recommendations
`
`A. Recommendation and Conclusion 011 Approvability
`
`Recommend to approve this NDA from CMC perspective.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Substance
`
`Travoprost is in a class of compounds known as prostaglandin. Prostaglandins are naturally
`occurring and by synthesis from unsaturated 20-carbon fatty acids, primarily arachidonic acids
`They are mediators of a diverse group of physiologic processes. Specifically, travoprost is a
`synthetic prostaglandin F2 uanalogue. TravOprost an isopropyl ester pro-drug,IS hydrolyzed by
`esterases in the cornea to its biologically active free acid The drug substance was approved
`. earlier under NDA 21-257, Travatan, and benzalkonium /disodium edetate containing
`preservative formulation. The same drug substanceis used1n this NDA but free of
`benzalkonium/disodium edetate.
`
`The drug substance is colorless yellow oil that is clear to slightly opalescent. It is practically
`insoluble in water and soluble in non~polar solvents, e.g., octanol, methanol. Travoprost is
`optically active and structurally well characterized. Although, synthesis is complex ems
`1
`
`NDA 21-994 Travatan '
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`
`’
`
`Page 9 of 73
`
`

`

` EMISTRY REVI’ ,.
`
`Executive Summary Section
`
`Drug Product
`
`Travoprost Ophthalmic solution, 0.004% (Travatan BAC-free) is a sterile, preserved aqueous
`solution formulated for topical application. The inactive components include polyoxyl 40
`- hydrogenated castor oil (HCO—40), propylene glycol, boric acid, sorbitol, zinc chloride, sodium
`hydroxide, hydrochloric acid, and purified water A W level of HCO-40 was used1n the
`
`formulationWWW Wfiw HCO—40 concentration is “W the
`concentration ofthe drug substanceAlthough HCO-40[S a USP Monograph,we”1W1...
`
`tam-L.'wwwWWW-flaw
`“wa.»
`mmwmmmmmmwAs a result, Alcon tests the
`raw material HCO-40 with the more restrictive specifications from JP, USP and Eur Phar. The
`drug concentration is same as that approved for benzalkonium chloride containing drug product
`
`Travatan under NDA 21-25 7. The product is packaged in a natural ,
`oolypropylene
`Warts...» bottle with a polypropylene (PP) natural plug and a turquoise (PP) closure. The pH of
`the solution is approximately-we: the solution is sterile and isotonic. The major manufacturing
`
`steps are:-'
`1‘
`granite“r:"H:
`
`(0’)”
`«v ”sags-«Wm313%112-6?’
`-a
`WWW“Sufficient information was provided to assess safety and set controls forleachables
`from the container closure and the label. The tests include assay and impurities for travoprost,
`assay for boric acid and zinc, and physical measurements, e.g., particulates, color, etc. The
`microbiological attributes include preservative effectiveness, sterility and container/closure
`integrity.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Travoprost free acid is a selective FP prostanoid receptor agonist which is believed to reduce
`intraocular pressure. Travoprost is used for the reduction of elevated intraocular pressure in
`patients with open-angle glaucoma or ocular hypertension. The ophthalmic solution is applied
`through a dropper.
`
`C. Basis for Approvability or Not-ApproVal Recommendation
`
`Travoprost was previously approved under NDA 21- 257 in benzalkonium/disodium edetate
`containing formulation. Benzalkonium/disodium cdetate can produce deleterious effect upon
`prolonged use Therefore, the proposed formulation is developed free of benzalkonium/disodium
`editate and having the same concentration of the drug substance and HCO-40 as inthe approved
` V-‘WWW‘
`
`“W‘W‘VWMWMWWW Thus the proposed
`1
`
`formulation13 an improvement from safetyconsideration for long term use The proposed
`manufacturing facilities have satisfactorily passed inspection by the Office of Compliance. Nine
`months stability data were provided to support .M shelf life. Alcon had updated the
`NDA 21-994 Travatan
`
`Jaw.»
`
`.
`
`m1manWe-WWMFL~310‘?NEm‘““"’3:""“3“me
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`
`‘
`
`Page 10 of 73
`
`

`

` WEMISTRY REVIE
`
`Executive Summary Section
`
`
`
`524:“.erA‘QK‘ACSm“Mk“
`
`time point, the samples stored at
`stability data to W on 9/1/06. At the‘
`
`”i‘WWWW RH showed particulates identified as the WW
`2.2.22 , (12awe
`.lots manufactured and tilled1n both2.5 mL and 5 mL bottle-s had
`
`particulate matter..
`WWWWWWWW
`,._
`1,.
`> a“”2 Travatan Z samples
`.
`,.
`stored up1}
`RH are free of particulates. The samples stored at‘"were
`at
`
`
`
`free of particulates at —-~————-and up to
`—- storage ~~""‘N’W’MW’W“WWW
`have low aqerus solubility. Therefore, the proposed strategy is to decrease the pH ofthe
`solution below pH ~1n order to eliminate particulates formed from
`“I« The.
`
`Specification for pH ofthe drug product solutionis tightened from r
`‘
`1nthe
`planned commercial batches; .W_W..,...2-2.2-2.“.1.,t- .
`
`.f‘
`
`FDA made the risk assessment and set
`to
`the shelf life as follows. Based on only wwwmw lots had particulates while the/«iots were
`free of particulates after storage for w- months at WWW” RH and that the drug product15
`planned to be stored at W‘at the distribution centers, a total of 14 monthshelf life was
`
`
`approved
`atmwmwcp
`-.
`.
`, 2.21.».
`dXE-anflm. 222723-5222
` r»
`a
`at»;.w)'V{www~1w~xr""~‘"V"
`
`The approved shelf lifeIS 14 months.
`23.. 7mm»;
`
`J
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Chemist Name/Date: Shrikant N. Pagay
`ChemistryTeamLeader Name/Date: Norman Schmuff
`Project Manager Name/Date: Michael Puglisi
`
`C. CC Block
`
`NDA 21—994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`Review #2
`.
`
`Page 11 of 73
`
`

`

`£2
`
`Page(s) Withheld
`
`\/
`
`Trade Secret / Cenfidential
`
`Draft Labeling
`
`Deliberative Process
`
`Withheld Track Number: Chemistry-
`
`‘
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Shrikant Pagay
`9/16/2006 04:33:24 PM
`CHEMIST
`
`Linda Ng
`9/18/2006 08:30:49 AM
`CHEMIST
`'
`’
`
`Signing for Norman
`
`Appears This Way
`On Original
`‘
`
`

`

`med&DwgmmmmflmMH
`
`Memorandum
`
`Date :
`
`September 12, 2006
`
`From:
`
`I
`
`Linda Ng, Ph.D.’
`'Pharmaceutical Assessment Lead for Ophthalmology
`
`Through: Elaine Morefield, Ph.D.
`Director, ONDQA Division II
`
`Subject:
`-
`To:
`
`(travoprost ophthalmic solution)
`NDA 21— 994, Travatan Z
`0.004%, Alcon Research Ltd
`The File
`
`Background
`
`\
`
`NDA 21— 994, Travatan Z (travoprost ophthalmic solution) 0.004% is
`being reviewed by Dr. Suresh Pagay, chemistry reviewer.
`He is on
`travel and I, as the acting Branch Chief,
`am addressing issues to
`complement Dr. Pagay's review #2.
`The PDUFA date is September 21,
`2006.
`'
`'
`
`¢-\
`
`Alcon Research Ltd submitted an amendment dated September 1, 2006
`
`to support
`the proposed expiration dating period of
`
`%RH
`the product
`stored. at
`"”"W"
`The
`'e»»
`__m, data at__ N~W“'
`failed the particulate matter criteria in “—“*out of
`-*< batches;
`
`
`and the
`smwwwm
`data at '
`'sRH failed in Prr’out of the
`in
`batches tested and failed the Visible particles in
`of the ~74
`~mm«mamwmw~«
`. Data at
`the refrigerated condition at —m———~,RH
`met all criteria of
`the drug product specificatiOn for the
`"“_
`batches
`
`Content
`
`the particulate is the insoluble .“émmwmmw
`According to Alcon,
`*“Mw””*““mwrmflwrnmmvwwmmmmflwv.
`The formation is due to interaction
`between memfiwamuv-ww‘v-"V‘r:17r_—~
`
`

`

`\
`
`Page(s) Withheld
`
`/ Trade Secret / Confidential
`
`Draft Labeling
`
`Deliberative Process
`
`Withheld Track Number: Chemistry— A
`
`

`

`—mmm-
`
`
`
`
`
`
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`“mm“mmmmmmmmmm—q
`
`Linda Ng
`9/12/2006 11:02:55 AM
`.
`CHEMIST
`'
`0ND PM to convey comments to applicant
`
`Elaine Morefield
`
`9/13/2006 12:57:06 PM
`CHEMIST
`
`Appears This Way
`On Original
`
`

`

`HEMISTRY REVIEW
`
`
`
`NDA 21-994
`
`TRAVATAN Z
`
`Travoprost ophthalmic solution, 0. 04%
`Alcon Inc.
`‘
`
`Shrikant N Pagay
`Anti-Infective and Ophthalmic Drug Products
`CMC REVIEW # 1
`’
`.
`
`"94
`
`Appears This Way
`On Original
`
`NDA 21-994 Travatan
`
`TravoproSt Ophthalmic Solution, 0.004%
`
`

`

`
`Table Of Contents
`
`Table of Contents
`
`...................2 ,
`
`Chemistry ReviewiDataSheet..............................4
`
`. The Executive Summary ................................
`
`.............9
`
`I. Recommendations ..............................................................................................................9
`
`A.Recommendation and Conclusion on Approvability ...................................................
`
`B Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable .........................................................
`
`II. Summary of Chemistry Assessments ......................_.........................................................9
`
`A. Description of the Drug Product(s) and Drug Substance(s) .....................................
`
`B. Description of How the Drug Product is Intended to be Used.................................'
`
`C. Basis for Approvability or Not-Approval Recommendation....:...............................
`
`III. Administrative"..-............................................................................................................ 11
`
`A. Reviewer’s Signature..................................................
`
`B. EndorsementBlock.........
`
`C. CC Block ........................................................................................................................
`
`Chemistry Assessment.................‘_......................................................................... 12‘
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of
`Data
`.....................'.............................................................................
`
`S DRUG SUBSTANCE [Name, Manufacturer] ......................................................... 12
`
`' P DRUG PRODUCT (Name, Dosage form] ............................................;................... 15
`
`A APPENDICES ................................................................................................................
`
`R REGIONAL INFORMATION................................................................................. 58
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ...........................
`
`NDA 21—994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`
`Jar
`’AI
`
`

`

`
`
`A. Labeling & Package Insert ..........................................................................................
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion
`
`III. List Of Deficiencies To Be Communicated .................................,...............................59
`
`Appears This Way
`On Original
`
`‘
`
`‘
`
`w""
`Neck'
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`
`fl
`
`I
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`

`

`
`
` HsEMISTRY REVIfE
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NBA 21—994
`
`2. REVIEW #1 1
`
`3. REVIEW DATE: 2/27/06
`
`4; REVIEWER: Shrikant N. Pagay
`
`5. PREVIOUS DOCUIVIENTS:_ I
`
`1
`
`V
`
`1
`
`Previous Documents
`
`None
`
`Document Date '
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 5) Reviewed
`Original
`Amendment
`
`_
`
`Amendment
`
`1
`
`.
`
`Document Date
`1 1/18/05
`12/14/05
`
`7/25/06
`
`Appears This Way
`On Original
`
`NDA 21—994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`
`V
`
`Page 4 of 63
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`

`

` EMISTRY REVIE
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`7. NAME & ADDRESS OF APPLICANT:
`
`Chemistry Review Data Sheet
`
`Name:
`
`-
`
`.
`
`Address:
`
`‘
`
`Alcon, Inc.
`Alcon Research, Ltd.
`Mail Code R7-18
`
`.
`
`6201 South Freeway
`Fort Worth, TX 76134—2099
`
`Representative: Angela Kothe
`
`Telephone 817- 551— 4933
`
`8. DRUG PRODUCT NAlVfE/CODE/TYPE:
`
`a). Proprietary Name: TRAVATAN® Z (travoprost ophthalmic solution, 0.004%) (Proposed)
`b). Non-Proprietary Name (USAN): Travoprost (USAN, BAN, JAN)
`c). Code Name/# (ONDC only): -
`.
`Company or Laboratory Code
`AL-6221 (Alcon)
`AL06221 (Alcon)
`.
`CH-4074 (Dow)
`' Other Nonproprietary Name(s): NA
`' Chemical Abstracts Service (CAS) Registry Number
`1'57283-68-6 '
`
`Type/Submission Priority (ONDC only):
`0 Chem. Type: 5
`
`0 Submission Priority: S
`
`‘9. LEGAL BASIS FOR SUBMISSION: 505 (b) (l)
`
`10. PHARMACOL. CATEGORY: Ophthalmic / Reduction of pressure in
`glaucoma or ocular pressure.
`
`.
`
`11. DOSAGE FORM: Sterile Solution
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
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`Page 5 of 63
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`

`

`EMISTRY REVIE
`
`Chemistry Review Data Sheet
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`12. STRENGTH/POTENCY: 0.004%
`
`13. ROUTE OF ADMINISTRATION: Ophthalmic
`
`14. Rx/OTC DISPENSED:
`
`X' Rx
`
`OTC
`
`15. SPOTS gSI’EClAL PRODUCTS ON—LINE TRACKING SYSTEM):
`.
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`l6. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`[lR-[la(Z),ZB(lE,3R *),3a,5a]]-7-[3,5-Dihydroxy-Z—[3—hydroxy-4-[3-_
`(trifluoromethyl)phenoxy]-1-butenyl]cy_clopentyl]e5-heptenoic acid, l-methylethylester
`
`(Z)-7—[(1R,2R,3R,5S)—3,5-Dihydroxy-2-[(l E,3R)—3-hydroxy-4~[(a,a,a-trifluoro-m-isopropyltolyl)
`oxy]- 1 -butenyl]cyclopentyl.]-5 -heptenoate
`
`Molecular Formula: C26H35F306
`
`' Relative Molecular Mass: 500.55
`
`
`
`Axr-vi'v"
`“A"
`
`Appears This Way
`On‘ Original
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`
`Page 6 of 63
`
`ii
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`\\
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`

`
`HQEMISTRY REVIJV
`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. D'MFs:
`
`
`
`
`
`‘
`
`“'7
`
`
`
`
`
`
`
`
` J
`
`i,
`
`
`lll_‘“l_7L
`
`1 Action codes for DMF Table:
`l —— 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)
`
`.
`
`2% _
`
`B. Other Documents:
`
`DOCUMENT
`
`NDA
`
`
`
`-
`APPLICATION NUMBER
`DESCRIPTION
`
`21-257
`
`Formulation of the same drug
`
`with preservative.
`
`
`
`
`
`
`123. STATUS:
`
`NDA 21—994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`
`it
`
`\\
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`Page 7 of 63
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`
`
`
`
`HOLDER
`
`
`ITEM
`.
`DATE
`REFERENCED
`CODEl
`STATUS2
`REVIEW
`
`COMPLETED
`
`
`
`
`
`COMMENTS
`~
`
`

`

` HEMISTRY REVICE'
`
`
`
`Chemistry Review Data Sheet
`
`CONSULTS/ CMC
`—
`RELATED
`RECOMMENDATION
`DATE
`
`REVIEWS
`‘
`Biometrics
`NA
`
`
`REVIEWER
`
`
`
`
`
`EES
`Acceptable
`12/20/05
`
`Pharm/Tox
`NA '
`
`
`Bi_oPharm
`NA
`_
`LNC
`Establish name
`
`negotiated
`
`
`Methods Validation
`
`OPDRA
`Trade name negotiated
`Pending
`EA
`Categorical Exemption
`12/ 15/05
`acce ted
`
`Microbiology
`Pending
`
`L.Ng
`
`
`
`
`19. COMMENTS: No Comments
`
`Appears This Way
`Qn Original
`
`NDA 21—9911 Travatan
`
`.
`
`Travoprost Ophthalmic Solution, 0.004%
`
`Page 8 0f 63
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`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 21-994
`
`The Executive Summafl
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`Recommend to approve this NDA from CMC perspective pending satisfactory review of
`microbiolOgy section by the OPS microbiologist, the trade name by the Division of Medication
`Errors and Technical Support and the establishment of the shelf life based on the observations in
`
`the samples stored for ‘
`under long term storage condition.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug’Substance(s)., :: :
`
`.:'
`
`1
`
`Drug Substance
`
`Travoprost is in a class of compounds known as prostaglandin. Prostaglandins are naturally
`occurring and by synthesis from unsaturated 20-carbon fatty acids, primarily arachchidonic
`acids. They are mediators of a diverse group of physiologic processes. Specifically, travoprost is
`a synthetic prostaglandin F2 uanalogue. Travoprost, an isop'ropyl ester pro-drug, is hydrolyzed by
`. esterases in the cornea to its biologically active free acid. The drug substance was approved
`earlier under NDA 21-25 7, Travatan, and benzalkonium Idisodium editate containing
`preservative forrnulation. The same drug substance is used in this NDA but free of
`benzalkonium/disodium editate.
`
`The drug substance is colorless yellow oil that is clear to slightly opal-escent. It is practically
`insoluble in water and soluble in non-polar solvents, e.g., octanol, methanol. Travaprost is
`
`optically active and structurally well characterized. Although, synthesis is comple‘ ~
`~—
`"l
`
`, the
`
`7
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`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`‘
`
`.
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`Page 9 of 63
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`

`

`
`
`Executive Summary Section
`
`Drug product
`
`Travoprost Ophthalmic solution, 0.004% (Travatan BAC-free) is a sterile, preserved aqueous
`solution formulated for topical application. The inactive components include polyoxyl 40
`hydrogenated castor oil (HCO—-40), propylene glycol boric acid, sorbitol, zinc chloride, sodium
`
`hydroxide hydrochloric acid, and purified water A
`of HCO—40 was used in the
`
`formulatiorWNW...
`1.1111111111111111. HCO-40 concentration is11.11.11.111.
`the
`concentration ofthe drug substance. Although HCO-'401s a USP Monograph,1..
`.1«z»: 11..
`’wwwwwwwaaa11W“11111111111me111.11.11.1111W»~anm As a result, Alcon tests the
`raw material HCO-40 with the more restrictive specifications from JP, USP and Eur Phar. The
`drug concentration is same as that approved for benzalkonium chloride containing drug product
`
`Travatan under NDA 21—257. The product15 packaged1n a natural
`polypropylene
`-——H""“ bottle with a polypropylene (PP) natural plug and a turquoise (PP) closure The pH of
`the solution15 approximately: amthe solution1s sterile and / he major manufacturing
`a.“ "1,1,
`,1
`“maun‘\-’ w :.—-:.-.~
`steps are WWmmmuw1.-.111m-..1m11mw.mmwmm
`:wwagxs‘..1»dezmfififlmfim‘mewnWWwme-Agmmm n.ans—.3, _1,1&1.w,a.u_:~=~‘
`
`7n
`mWsufficient information Was provided to assess safety and set controls for leachables
`from the container closure and the label. The tests include assay and impurities for travoprost,
`assay for boric acid and zinc, and physical measurements, e. g. particulates, color, etc. The
`microbiological attributes include preservative effectiveness, sterility and container/closure
`integrity.
`
`B. ' Description of How the Drug Product is Intended to be Used
`
`Travoprost free acid is a selective FP prostanoid receptor agonist which is believed to reduce
`intraocular pressure. Travoprost is used for the reduction of elevated intraocular pressure in
`patients with open-angle glaucoma or ocular hypertension. The ophthalmic solution is applied
`through a dropper.
`‘
`
`R
`«we-
`
`C. Basis for Approvability or Not—Approval Recommendation
`
`Travoprost was previously approved under NDA 21- 257 in benzalkonium/disodium editate
`containing formulation. Benzalkonium/disodium editate can produce deleterious effect upon
`prolonged use. Therefore, the proposed formulation is developed free of benzalkonium/disodium
`editate and having the same concentration of the drug substance and HCO-40 as in the approved
`
`formUlathfl The pl‘OPOSCd formulation contains” ~
`.
`wa”WWW“We-““‘Vmwnamamaammmi
`QOvan—Mn-141'9"“H'4 1 "
`1
`“a.1WW"WWWwamwwa-wwamxmewufi*TIWWWWW
`
`I
`11-mamam.‘VM“
`
`
`‘
`”MWWW-1,.
`‘
`"mu"
`
`"Wm—zm—”5‘er'm
`*vm’pav’.1“?»Nu—“v:~4 ~92-1 r;w ‘
`_ -
`““ The data15 satisfactory for- -
`shelf
`life The proposedmanufacturingfacilities have satisfactorily passed inspection by the Office of
`Compliance. Thus the proposed formulation15 an improvement from safety consideration for
`long term use and satisfactory from the quality consideration.
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`
`Page 10 of 63
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`

`
`
`Executive Summary Section
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Chemist Name/Date: Shrikant N. Pagay
`ChemistryTeamLeader Name/Date: Norman Schmuff
`Project Manager Name/Date: Michael Puglisi
`
`C. CC Block
`
`Appears This WW
`On Original
`
`NDA 21-994 Travatan
`
`Travoprost Ophthalmic Solution, 0.004%
`
`Page 11 of 63'
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`

`

`52.
`
`Page(s) Withheld
`
`/ Trade Secret / Confidential
`
`Draft Labeling I
`
`Deliberative Process
`
`Withheld Track Number: Chemistry— 3
`
`'
`
`

`

`---------—-——-—--———¢--------——---_--__-_--_-----——--------------_-----_-__--_--—-—---—-------—-—------------........
`
`ThisIs a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`----------------q_-_----__-__-_----_-_-__-_-------_—---_---__--------------------------------------------------------
`
`Shrikant Pagay
`8/25/2006 08:59:24 AM
`CHEMIST
`
`Norman Schmuff
`
`8/29/2006 10:40:05 AM
`CHEMIST
`-
`
`AppearsThis Woy
`(On Original
`
`qg
`
`