`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`202514Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`NDA 202-514
`
`ZIOPTANTM (tafluprost ophthalmic solution) 0.0015%
`
`Merck Sharp & Dohme Co
`
`Maotang Zhou, Ph.D.
`
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment II
`Branch V
`
`CMC REVIEW OF NDA 202-514
`
`For the Division of Transplant and Ophthalmology Products
`
`Reference ID: 3080223
`
`

`

`
`
`CMC Review Data Sheet
`
`1. NDA 202-514
`
`2. REVIEW #2 3
`
`3. REVIEW DATE: 30-Jan-2012
`
`4. REVIEWER: Maotang Zhou, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Original IND 62,690 submission
`Original IND 62,690 CMC review
`End-of-phase-Z meeting (No CMC issues discussed)
`Pre—NDA meeting
`
`Document Date
`
`23-May-2001
`23—July—2001
`24-Aug-2009
`l3-Aug- 1010
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`DARRTS
`
`Document Date
`
`Stamp Date
`
`07-JAN-201 1
`
`28-APR-201 l
`
`08-JUN-201 l
`
`W
`l JUN-2011
`
`-2011
`-OI;
`-2011
`I
`26 JUL-201 l
`
`EIv
`
`0020
`0024
`
`0025
`
`0026
`
`01 -AUG-201 l
`
`0027
`
`lO-AUG-201 l
`
`0030
`
`0046
`0047
`0050
`
`22—Aug—201 l
`
`5-Dec-201 l
`7-Dec-201 l
`2-Jan-2012
`
`—
`
`Oi .
`
`Submission(s) Reviewed
`
`Ori - inal NDA Submission
`
`SD
`Number
`0000
`
`Quality Amendment (Response to Agency
`0 estions
`
`Quath Amendment (Response to Agency
`0 estions
`
`Quath Amendment (Response to Agency
`0 estions
`ethod Validation Re - . rts
`0
`.li Amendment
`Amendment
`’ es - onse to 05/11/2011 CMC IR
`
`Quality Amendment (Response to Information
`R t uest
`
`Quality Amendment (Response to Information
`R uest
`
`Quality Amendment (Response to Information
`R I uest
`
`Quality Amendment (Response to Information
`R o nest
`General Cones » .ndence
`General Cones » .ndence
`Resubmission/Class 1
`
`Referenoe ID: 3080223
`
`

`

`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Merck Sharp & Dohme Corp.
`126 Lincoln Avenue
`
`PO. Box 2000
`
`Mail Drop: RY33-204
`Rahway, NJ 07065-0900
`Chitkala Kalidas, Ph.D.
`732—594-0599
`
`Representative:
`Telephone:
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Tafluprost
`b) Non-Proprietary Name: Tafluprost
`c) Code Name/# (ONDQA only): AFP—l68
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: Prostaglandin analogue
`
`0 Submission Priority: Stande
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY:
`
`11. DOSAGE FORM:
`
`Sterile Ophthalmic Solution
`
`12. STRENGTH/POTENCY: 0.0015%
`
`13. ROUTE OF ADMINISTRATION: Topical
`
`14. Rx/OTC DISPENSED:
`
`‘1 Rx
`
`OTC
`
`15. SPOTS QSPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`SPOTS product — Form Completed
`
`
`‘1
`Not a SPOTS product
`
`l6. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name: l-methylethyl (5Z)-7-{(1R, 2R, 3R, SS)-2-[(lE)-3,3—difluoro—4—
`phenoxy— l-butenyl]-3,5-dihydroxycyclopentyl}-5-heptenoate
`Molecular Formula: C25Hs4F205
`
`Reference ID: 3080223
`
`

`

`
`
`Molecular Weigl_1t: 452.53
`
`Chemical Structure:
`
`H0
`
`t “‘\=/\/Io\r
`HO
`F FA
`VI
`
`A. DMFs:
`
`
`
`ITEM
`REFERENCED
`
` HOLDER
`
`
`7/25/201 1-m-
`
`---
`
`
`
`
`DATE
`
`
`
`STATUS2
`
`REVIEW COMMENTS
`COMPLETED
`
`
`
`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)
`
`B. Other Documents:
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`62690
`
`-EL1-
`
`Reference ID: 3080223
`
`

`

`
`
`18. STATUS:
`
`ONDQA: Approvable pending resolution of microbiology deficiencies.
`
`CONSULTS/ CMC
`RELATED REVIEWS
`Biometrics
`EES
`Pharm/Tox
`
`RECONIMENDATION
`N/A
`Overall Acc table
`N/A
`
`DATE
`
`N/A
`13-0ct-201 l
`N/A
`
`Bio ohann
`LNC
`
`N/A
`N/A
`
`N/A
`N/A
`
`Methods Validation
`
`N/A. according to the
`current 0ND I A olic
`
`
`
`M Stock
`N/A
`
`N/A
`
`r0 trier
`
`name
`
`acc table see review
`
`recommended for a I .roval
`
`*DMEPA: Division of Medication Error Prevention and Analysis
`
`Reference ID: 3080223
`
`

`

`
`
`The CMC Review for NDA 202-514
`
`The Executive Summafl
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The CMC information as provided in the NDA is adequate to assure the identity,
`strength, purity, and quality of the drug product. An “Acceptable” site
`recommendation from the Office of Compliance has been made. The labels have
`adequate information as required. Therefore, from a CMC perspective, this NDA
`is recommended for approval.
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None
`
`II. Summary of CMC Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`(1) General
`
`NDA 202—5 14 is submitted by Merck Sharp & Dohme Corporation to seek
`approval of a preservative free formulation of 0.0015% tafluprost ophthalmic
`solution for the reduction of elevated intraocular pressure in open angle glaucoma
`and ocular hypertension. Tafluprost (MK-2452), a new molecular entity, is an
`analogue of prostaglandin F201 (PGF2a). Tafluprost is rapidly hydrolyzed by
`corneal esterases to the biologically active metabolite, tafluprost acid. Tafluprost
`0.0015% preservative free (PF) and preservative containing (PC) formulations are
`currently approved in several other countries.
`
`(2) Drug Substance
`
`The drug substance, tafluprost, is a colorless to light yellow viscous liquid, with a
`molecular formula of C25H34F205 and a molecular weight of 453.53 Daltons.
`Tafluprost is a new molecular entity (NME) and it has not been previously
`marketed in the United States. Tafluprost is manufactured, controlled, packaged,
`and stability-tested at
`M".
`The information on
`manufacturing processes and controls for tafluprost is described in
`(no) DMF
`M”. A letter of authorization to refer to DMF
`one was provided on behalf of
`mo DIVIF
`one has been reviewed and all chemistry issues
`
`Reference ID: 3080223
`
`

`

`
`
`have been resolved. As revised, the DMF is adequate to support the current
`NDA.
`
`(3) Drug Product
`
`The drug product, tafluprost 0.0015% ophthalmic solution is a sterile aqueous
`isotonic solution that contains the drug substance tafluprost and the excipients,
`sodium dihydrogen phosphate dihydrate, polysorbate 80, disodium edetate,
`glycerol, sodium hydroxide and/or hydrochloric acid, and water for injection.
`Glycerol is used to
`M of the drug product. Sodium hydroxide and
`hydrochloric acid are used to adjust the solution pH to 5.5 — 6.7. All the excipients
`are of compendial grade (USP/NF).
`
`M0 by
`The drug product solution is manufactured,
`Laboratoire Unither, France. The drug product manufacturing process (we
`
`. Each single—use ampoule is filled with 0.3 mL of the sterile solution
`containing 4.5 pg of tafluprost and affixed with a label. The labeled ampoules are
`packed in
`“m pouches, 10 ampoules
`per pouch. The pouches are then packed in carton boxes. Commercial cartons are
`either 30—count (3 pouches) or 90-count (9 pouches) and sample cartons are 10-
`count (1 pouch).
`
`At the time of the NDA submission, 18-month long term and 6-month accelerated
`stability data were provided from three registration stability batches. The stability
`testing of these batches is expected to continue to 36 months. In addition, 36-
`month long term and 6 month accelerated stability data from 3 batches were also
`provided. The available stability data support the proposed drug product shelf life
`of 36 months when stored in cold (2-8 °C) protected from moisture. The single-
`dose ampoules have to be stored in the
`M” pouch to prevent water
`evaporation. The results from in-use studies support the proposed statement:
`M4)
`
`The applicant did not discuss their control strategy in the NDA. Based on this
`reviewer’s evaluation of the NDA information, the following conventional control
`strategies are used for product quality assurance by the applicant and these appear
`to be adequate for product quality assurance.
`0 Use of excipients commonly used in ophthahnic products with
`excipient quality controlled by adherence to compendial specifications
`0 Use of critical process parameter ranges and in-process testing
`specification to control the manufacturing process
`Inclusion of secondary packaging for protection from light and water loss
`
`0
`
`Reference ID: 3080223
`
`

`

`
`
`0 Release testing of final drug product for critical product attributes such as
`appearance, identity, osmolality, pH, assay, purity, sterility, endotoxin,
`and particulate matter.
`
`During the first review cycle, the NDA as amended provided sufficient and
`adequate information on raw material controls, manufacturing processes and
`process controls, specifications for assuring consistent product quality of the drug
`substance and drug product, and sufficient stability information on the drug
`product to support the proposed expiry period. All facilities were found
`“Acceptable” by the Office of Compliance and all labels were reviewed and found
`to have the required information. The product quality microbiology reviewer, Dr.
`Jessica Cole, found the NDA deficient due to inappropriate sterility validation.
`This deficiency resulted in the NDA receiving an action of “Complete Response”
`the first review cycle. The complete response letter was issued on November 7,
`2011. The NDA was resubmitted on January 13, 2012 with appropriate sterility
`validation data. This information was found satisfactory by the product quality
`microbiology reviewer, Dr. Jessica Cole, who has now recommended the NDA
`for approval. All pending CMC issues are now resolved.
`
`B. Description of How the Drug Product is Intended to be Used
`
`ZioptanTM (tafluprost) is a sterile, preservative-free, clear, colorless, isotonic
`ophthalmic solution containing tafluprost 0.0015% (15 ug/mL) intended for
`topical administration to the eye. The recommended dose is one drop per affected
`eye once daily in the evening. The applicant seeks approval of tafluprost
`ophthahnic solution, 0.0015% for a once daily dosing regimen for the reduction of
`elevated intraocular pressure in open-angle glaucoma or ocular hypertension.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`During the first review cycle, this NDA was recommended for approval in CMC
`Review #2 dated October 24, 2011, contingent upon satisfactory resolution of all
`pending product quality microbiology deficiencies. On January 13, 2012, the
`applicant filed a Class 1 resubmission with the requested quality microbiology
`data. The product quality microbiology reviewer, Dr. Jessica Cole, has reviewed
`the data and found the data acceptable. On January 17, 2012, Dr. Cole has
`recommended the application for approval in Product Quality Microbiology
`Review #3. As a result, all pending CMC issues have been resolved.
`
`In summary, the NDA has provided sufficient information on raw material
`controls, manufacturing processes and process controls, specifications,
`microbiology and endotoxin attributes and stability information to assure strength,
`purity, and quality of the drug product during the expiration dating period. All
`facilities have “Acceptable” site recommendations. All labels have the required
`information. Therefore, from the CMC perspective, NDA 202-514 is
`recommended for approval.
`
`Reference ID: 3080223
`
`

`

`
`
`III. Administrative
`
`A. Reviewer’s Signature:
`(See appended electronic signature page)
`
`Maotang Zhou, Ph.D., Reviewer, ONDQA
`
`B. Endorsement Block:
`
`(See appended electronic signature page)
`
`Rapti Madurawe, Ph.D., Branch Chief, Branch V, Division of New Drug
`Quality Assessment 11, ONDQA
`
`C. CC Block: entered electronically in DARRTS
`
`Reference ID: 3080223
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MAOTANG ZHOU
`01/31/2012
`
`RAPTI D MADURAWE
`01/31/2012
`
`Reference ID: 3080223
`
`

`

`MEMORANDUM
`
`Date: November 1, 2011
`
`To: NDA 202-514
`
`From: Terrance Ocheltree, Ph.D., R.Ph.
`Director
`Division of New Drug Quality Assessment II
`ONDQA
`
`
`Subject: Tertiary review of ONDQA recommendation for NDA 202-514, tafluprost ophthalmic
`solution, 0.0015%, ZIOPTAN™.
`
` have assessed the ONDQA reviews of NDA 202-514 by Maotang Zhou, Ph.D. The initial
`ONDQA CMC review was entered into DARRTS on August 26, 2011, with a recommendation
`for a Complete Response due to an absence of a recommendation from the Office of Compliance
`on the manufacturing and testing sites acceptability and pending labeling issues. A second CMC
`review was entered into DARRTS on October 24, 2011 by Dr. Zhou updating the status of the
`recommendation from the Office of Compliance and adding the recommendation of “Approvable
`pending resolution of microbiology deficiencies” from the Product Quality Microbiology
`Reviewer. On October 13, 2011 the Office of Compliance entered an Overall Recommendation
`of “Acceptable” into EES. However, due to the Product Quality Microbiology Review, the
`ONDQA recommendation remains Complete Response. An ONDQA Biopharmaceutics review
`was not performed for this NDA.
`
` I
`
` I
`
` concur with the determination that the information as provided in the NDA is adequate to
`assure the identity, strength, purity, and quality of the drug product and support the
`recommendation of a drug product shelf life of 36 months for the proposed commercial product
`when it is stored in cold (2-8 ºC) environment and protected from moisture.
`
` was reviewed for the drug substance, tafluprost, and found
`The Drug Master File (DMF)
`to be ADEQUATE on July 25, 2011 by Dr. Zhou to support This NDA
`
`Secondary review of the CMC reviews was performed by Rapti Madurawe, Ph.D.
`
`
`
`Reference ID: 3040482
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TERRANCE W OCHELTREE
`11/07/2011
`
`Reference ID: 3040482
`
`

`

`
`
`NDA 202-514
`
`ZIOPTANTM (tafluprost ophthalmic solution) 0.0015%
`
`Merck Sharp & Dohme Co
`
`Maotang Zhou, Ph.D.
`
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment II
`Branch V
`
`CMC REVIEW OF NDA 202-514
`
`For the Division of Transplant and Ophthalmology Products
`
`Reference ID: 30301 78
`
`

`

`
`
`CMC Review Data Sheet
`
`1. NDA 202-514
`
`2. REVIEW #2 2
`
`3. REVIEW DATE: 17-Oct-2011
`
`4. REVIEWER: Maotang Zhou, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Original IND 62,690 submission
`Original IND 62,690 CMC review
`End-of-phase-Z meeting (No CMC issues discussed)
`Pre—NDA meeting
`
`Document Date
`
`23-May-2001
`23—July—2001
`24-Aug-2009
`l3-Aug- 1010
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`DARRTS
`
`Document Date
`
`Stamp Date
`
`O7-JAN-201 l
`
`28-APR-20 1 1
`
`08-JUN-201 l
`
`1 wJUN—2011
`
`JUN-2011
`—2011
`
`EIv
`
`-O
`26—JUL—201 l
`
`0026
`
`01-AUG-201 1
`
`0027
`
`0030
`
`22-Aug-201 1
`
`lO—AUG—201 1 hhh888z:3;LIL
`
`SD
`5E
`N
`0000
`
`0020
`0024
`
`0025
`
`Submission(s) Reviewed
`
`Original NDA Submission
`Quality Amendment (Response to Agency
`
`Quality Amendment (Response to Agency
`
`Quath Amendment (Response to Agency
`
`Quality Amendment (Method Validation Reports)
`Amendment (Response to 05/1 1/2011 CMC IR)
`Quality Amendment (Response to Information
`Request)
`Quality Amendment (Response to Information
`Request)
`Quality Amendment (Response to Information
`Request)
`Quality Amendment (Response to Information
`Request)
`
`Reference ID: 30301 78
`
`

`

`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Merck Sharp & Dohme Corp.
`126 Lincoln Avenue
`
`PO. Box 2000
`
`Mail Drop: RY33-204
`Rahway, NJ 07065-0900
`Chitkala Kalidas, Ph.D.
`732—594-0599
`
`Representative:
`Telephone:
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Tafluprost
`b) Non-Proprietary Name: Tafluprost
`c) Code Name/# (ONDQA only): AFP—l68
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: Prostaglandin analogue
`
`0 Submission Priority: Stande
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY:
`
`11. DOSAGE FORM:
`
`Sterile Ophthalmic Solution
`
`12. STRENGTH/POTENCY: 0.0015%
`
`13. ROUTE OF ADMINISTRATION: Topical
`
`14. Rx/OTC DISPENSED:
`
`‘1 Rx
`
`OTC
`
`15. SPOTS QSPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`SPOTS product — Form Completed
`
`
`‘1
`Not a SPOTS product
`
`l6. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name: l-methylethyl (5Z)-7-{(1R, 2R, 3R, SS)-2-[(lE)-3,3—difluoro—4—
`phenoxy— l-butenyl]-3,5-dihydroxycyclopentyl}-5-heptenoate
`Molecular Formula: C25Hs4F205
`
`Reference ID: 30301 78
`
`

`

`
`
`Molecular Weigl_1t: 452.53
`
`Chemical Structure:
`
`H0
`
`t “‘\=/\/Io\r
`HO
`F FA
`VI
`
`A. DMFs:
`
`COMPLETED 7/25/201 1
`
`DATE
`
`STATUS2
`
`REVIEW COMMENTS
`
`---
`
`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)
`
`B. Other Documents:
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`62690
`
`-EL1-
`
`Reference ID: 30301 78
`
`

`

`
`
`18. STATUS:
`
`ONDQA: Approvable pending resolution of microbiology deficiencies.
`
`CONSULTS/ CMC
`RELATED REVIEWS
`Biometrics
`EES
`Pharm/Tox
`
`RECONIMENDATION
`N/A
`Overall Acc table
`N/A
`
`DATE
`
`N/A
`13-0ct-201 l
`N/A
`
`Bio ohann
`LNC
`
`N/A
`N/A
`
`N/A
`N/A
`
`Methods Validation
`
`N/A. according to the
`current 0ND I A olic
`
`M Stock
`N/A
`
`N/A
`
`
`
`A
`
`Microbiology
`
`r0 trier
`
`name
`
`acc table see review
`
`Approvable pending
`resolution of microbiology
`deficiencies
`
`30—Sep—2011
`
`J Cole
`
`*DMEPA: Division of Medication Error Prevention and Analysis
`
`Reference ID: 30301 78
`
`

`

`
`
`The CMC Review for NDA 202-514
`
`The Executive Summafl
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The CMC information as provided in the NDA is adequate to assure the identity,
`strength, purity, and quality of the drug product. An “Acceptable” site
`recommendation from the Office of Compliance has been made. However, the
`product quality microbiology reviewer has made the recommendation of
`“Approvable pending resolution of microbiology deficiencies”. Therefore, from
`the CMC perspective, this NDA is not recommended for approval until all
`pending product quality microbiology deficiencies are satisfactorily resolved.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None
`
`II. Summary of CMC Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`(1) General
`
`NDA 202—514 is submitted by Merck Sharp & Dohme Corporation to seek
`approval of a preservative free formulation of 0.0015% tafluprost ophthalmic
`solution for the reduction of elevated intraocular pressure in open angle glaucoma
`and ocular hypertension. Tafluprost (MK-2452), a new molecular entity, is an
`analogue of prostaglandin F201 (PGFZa). Tafluprost is rapidly hydrolyzed by
`corneal esterases to the biologically active metabolite, tafluprost acid. Tafluprost
`0.0015% preservative free (PF) and preservative containing (PC) formulations are
`currently approved in several other countries.
`
`(2) Drug Substance
`
`The drug substance, tafluprost, is a colorless to light yellow viscous liquid, with a
`molecular formula of C25H34F205 and a molecular weight of 453.53 Daltons.
`Tafluprost is a new molecular entity (NME) and it has not been previously
`marketed in the United States. Tafluprost is manufactured, controlled, packaged,
`and stability-tested at
`_
`(”m The information on
`manufacturing processes and controls for tafluprost is described in
`“""DMF
`
`Reference ID: 30301 78
`
`

`

`
`
`one was provided on behalf of
`(no) A letter of authorization to refer to DMF
`”‘4’ DMF
`(mo has been reviewed and all chemistry issues
`have been resolved. As revised, the DMF is adequate to support the current
`NDA.
`
`(3) Drug Product
`
`The drug product, tafluprost 0.0015% ophthalmic solution is a sterile aqueous
`isotonic solution that contains the drug substance tafluprost and the excipients,
`sodium dihydrogen phosphate dihydrate, polysorbate 80, disodium edetate,
`glycerol, sodium hydroxide and/or hydrochloric acid, and water for injection.
`Glycerol is used to
`(”mof the drug product. Sodium hydroxide and
`hydrochloric acid are used to adjust the solution pH to 5.5 — 6.7. All the excipients
`are of compendial grade (USP/NF).
`
`“""by
`The drug product solution is manufactured,
`Laboratoire Unither, France. The drug product manufacturing process
`
`(m4) Each single-use ampoule is filled with 0.3 mL of the sterile solution
`containing 4.5 pg of tafluprost and affixed with a label. The labeled ampoules are
`packed in
`“’wpouches, 10 ampoules
`per pouch. The pouches are then packed in carton boxes. Commercial cartons are
`either 30—count (3 pouches) or 90—count (9 pouches) and sample cartons are 10-
`count (1 pouch).
`
`At the time of the NDA submission, 18-month long term and 6-month accelerated
`stability data were provided from three registration stability batches. The stability
`testing of these batches is expected to continue to 36 months. In addition, 36-
`month long term and 6 month accelerated stability data from 3 batches were also
`provided. The available stability data support the proposed drug product shelf life
`of 36 months when stored in cold (2-8 °C) protected fiom moisture. The single-
`dose ampoules have to be stored in the
`(mo pouch to prevent water
`evaporation. The results from in—use studies support the proposed statemenbtzw
`
`The applicant did not discuss their control strategy in the NDA. Based on this
`reviewer’s evaluation of the NDA information, the following conventional control
`strategies are used for product quality assurance by the applicant and these appear
`to be adequate for product quality assurance.
`
`0 Use of excipients commonly used in ophthalmic products with
`excipient quality controlled by adherence to compendial specifications
`
`0 Use of critical process parameter ranges and in-process testing
`specification to control the manufacturing process
`
`Reference ID: 30301 78
`
`

`

` 0
`
`Inclusion of secondary packaging for protection from light and water loss
`Release testing of final drug product for critical product attributes such as
`appearance, identity, osmolality, pH, assay, purity, sterility, endotoxin,
`and particulate matter.
`
`During review, discrepancies were noted in some data and information provided
`in the NDA. Additional information provided by the applicant relating to these
`issues was reviewed, and as presented, is satisfactory. The CMC information as
`provided in the NDA is adequate to assure the identity, strength, purity and
`quality of the drug product. On September 30, 2011, the product quality
`microbiology reviewer made the recommendation of “Approvable pending
`resolution of microbiology deficiencies”. Therefore, from the CMC perspective,
`this NDA is not recommended for approval until all pending product quality
`microbiology deficiencies are satisfactorily resolved.
`
`B. Description of How the Drug Product is Intended to be Used
`
`ZioptanjM (tafluprost) is a sterile, preservative-free, clear, colorless, isotonic
`ophthalmic solution containing tafluprost 0.0015% (15 ug/mL) intended for
`topical administration to the eye. The recommended dose is one drop per affected
`eye once daily in the evening. The applicant seeks approval of tafluprost
`ophthahnic solution, 0.0015% for a once daily dosing regimen for the reduction of
`elevated intraocular pressure in open—angle glaucoma or ocular hypertension.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`In CMC review #1 dated August 25, 2011, this NDA was recommended for
`approval contingent upon the following pending issues being satisfactorily
`resolved: (1) Overall site recommendation: Office of Compliance has not yet
`issued an overall acceptable site recommendation in EES; (2) Labeling: The
`review team has not yet initiated labeling negotiations
`
`On October 13, 2011, the Office of Compliance made an overall recommendation
`of “Acceptable” for the facilities related to the NDA (See the attached establish
`evaluation report). The labeling changes recommended by ONDQA have been
`forwarded to the applicant by the FDA review team (See CMC Assessment in this
`review). However, on September 30, 2011, the product quality microbiology
`reviewer made the recommendation of “Approvable pending resolution of
`microbiology deficiencies” (See Dr. Jessica Cole’s Product Quality Microbiology
`Review in DARRTS). Therefore, from the CMC perspective, this NDA is not
`recommended for approval until all pending product quality microbiology
`deficiencies are satisfactorily resolved.
`
`Reference ID: 30301 78
`
`

`

`
`
`HI. Administrative
`
`A. Reviewer’s Signature:
`(See appended electronic signature page)
`
`Maotang Zhou, Ph.D., Reviewer, 0NDQA
`
`B. Endorsement Block:
`
`(See appended electronic signature page)
`
`Rapti Madurawe, Ph.D., Branch Chief, Branch V, Division of New Drug
`Quality Assessment II, 0NDQA
`
`C. CC Block: entered electronically in DARRTS
`
`
`
`Reference ID: 3030178
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MAOTANG ZHOU
`10/17/2011
`
`RAPTI D MADURAWE
`10/24/2011
`
`Reference ID: 3030178
`
`

`

`
`
`NDA 202-514
`
`ZIOPTANTM (tafluprost ophthalmic solution) 0.0015%
`
`Merck Sharp & Dohme Co
`
`Maotang Zhou, Ph.D.
`
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment II
`Branch V
`
`CMC REVIEW OF NDA 202-514
`
`For the Division of Transplant and Ophthalmology Products
`
`Reference ID: 3006655
`
`

`

`
`
`Table of Contents
`
`CMC Review Data Sheet4
`
`The Executive Summary .........................................................................................8
`
`1. Recommendations ...................................................................................................................... 8
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 8
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps. if Approvable ................................................................................................... 8
`
`II. Summary of CMC Assessments ................................................................................................ 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 8
`
`B. Description of How the Drug Product is Intended to be Used ....................................................... 10
`
`C. Basis for Approvability or Not-Approval Recommendation ......................................................... 10
`
`III. Administrative .......................................................................................................................... 10
`
`CMC Assessment........................................................................... ......................... 11
`
`1. Review Of Common Technical Document—Quality (Ctd—Q) Module 3.2: Body Of Data ....... 1 l
`
`S. DRUG SUBSTANCE .................................................................................................................... 11
`S. 1
`General Information ........................................................................................................................ 11
`Nomenclature............................................................................................................................................. l 1
`Structure..................................................................................................................................................... 11
`
`S. 1.1
`8.1.2
`
`8 1.3
`8.2
`8.2.1
`
`General Properties...................................................................................................................................... 11
`Manufacture .................................................................................................................................... 12
`Manufacturers ............................................................................................................................................ 12
`
`8.2.2
`8.2.3
`
`8.2.4
`8.2.5
`
`Description of Manufacturing Process and Process Controls..................................................................... 12
`Control of Materials ................................................................................................................................... 13
`
`Controls of Critical Steps and Intermediates .............................................................................................. 13
`Process Validation and/or Evaluation ........................................................................................................ 13
`
`8.2.6
`8.3
`8.3.1
`
`Manufacturing Process Development ........................................................................................................ 13
`Characterization .............................................................................................................................. 13
`Elucidation of Structure and other Characteristics ..................................................................................... 13
`
`8.3.2
`8.4
`8.4.1
`8.4.2
`8.4.3
`8.4.4
`8.4.5
`8.5
`
`S.6
`s.7
`8.7.]
`8.7.2
`S 7.3
`
`Impurities ................................................................................................................................................... 13
`Control of Drug Substance .............................................................................................................. 13
`Specification .............................................................................................................................................. 13
`Analytical Procedures ................................................................................................................................ 14
`Validation of Analytical Procedures .......................................................................................................... 15
`Batch Analyses .......................................................................................................................................... 15
`Justification of Specification ...................................................................................................................... 15
`Reference Standards or Materials ................................................................................................... 16
`
`Container Closure System............................................................................................................... 16
`Stability ........................................................................................................................................... 16
`Stability Summary and Conclusions .......................................................................................................... 16
`Postapproval Stability Protocol and Stability Commitment ....................................................................... 16
`Stability Data ............................................................................................................................................. 16
`
`P. DRUG PRODUCT ........................................................................................................................ 17
`
`Reference ID: 3006655
`
`Page 2 of 77
`
`CMC Review #1
`
`

`

`
`
`Description and Composition of the Drug Product ......................................................................... 17
`P. 1
`Pharmaceutical Development.......................................................................................................... l7
`P2
`Components of the Drug Product............................................................................................................... l7
`P.2.l
`P.2.l.l Drug Substance...................