CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22-228
`
`APPLICA TI0N NUMBER:
`
`
`
`
`
`
`CHEMISTRY REVIEW(S)
`CHEMISTRY REVIEW! S}
`
`
`22-228
`
`

`

`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`NDA 22-288
`
`Bepotastine Besilate 1.5% Ophthalmic Solution
`
`
`ISTA Pharmaceuticals, Inc.
`
`
`
`Shrikant Pagay
`ONDQA/OPS/DAIOP
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`I. 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 - NA..........................................................................................8
`
`II. Summary of Chemistry 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..........................................................9
`C. Basis for Approvability or Not-Approval Recommendation............................................................9
`
`III. Administrative............................................................................................................................9
`A. Reviewer’s Signature........................................................................................................................9
`B. Endorsement Block.........................................................................................................................10
`C. CC Block........................................................................................................................................10
`
`Chemistry Assessment...................................................................................................................11
`Draft Comment:....................................................................................................................................12
`Attachment A .......................................................................................................................................13
`
`
`
`
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`Chemistry Review Data Sheet
`
`
`
`
`1. NDA #22-288
`
`
`2. REVIEW #: 3 (Methods validation only)
`
`
`3. REVIEW DATE: 2-September-2009
`
`
`4. REVIEWER: Shrikant Pagay
`
`
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`IND 66,864/ Original
`Amendment
`
`
`
`
`
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`Original NDA
`Amendment
`Amendment
`Amendment
`Amendment
`
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`Document Date
`12/20/06/
`9/10/08
`
`Document Date
` 11/12/08
`12/10/08
`7/2/09
`7/8/09
`7/31/09
`
`
`Name:
`
`ISTA Pharmaceuticals Inc
`
`Page 3 of 14
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Address:
`
`15295 Alton Parkway, Irvine, CA 92618
`
`Representative:
`
`Paul Nowacki, Director, Regulatory Affairs
`
`Telephone:
`
`949-789-3109
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`a) Proprietary Name: Bepreve
`b) Non-Proprietary Name (USAN): Bepotastine Besilate
`c) Code Name/# (ONDC only):TAU-284; SNJ-1773
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 1
`• Submission Priority: S
`
`
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b) (1)
`
`
`10. PHARMACOL. CATEGORY: Allergic Conjunctivitis
`
`
`11. DOSAGE FORM: Solution
`
`
`12. STRENGTH/POTENCY: 1.5% by weight
`
`
`
`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
`
`Page 4 of 14
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`Proposed Name:
`
`USAN Name: (+) -4-[[(S) p-Chloro-alpha -2-pyridylbenzyl] oxy]-1-piperidine
`butyric acid monobenzenesulfonate
`
`
`
`
`
`
`
`S
`
`
`
`H
`25
`
`ClN
`2
`
`O
`3
`
`•C
`6
`
`H
`6
`
`O
`3
`
`21
`
` C
`
`
`MW: 547.06
`
`Free acid Bepotastine MW. 388.90
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`Page 5 of 14
`
`

`

`
`
`
`
`
`A. DMFs:
`
`
`
`
`
`TYPE HOLDER
`
`Ube
`Industries
`Ltd.
`
`II
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`DMF
`#
`19966
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`ITEM
`REFERENCED
`Bepotastine
`besilate
`
`CODE1
`
`STATUS2
`
`1
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`Adequate
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`DATE
`REVIEW
`COMPLETED
`4/4/09
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`COMMENTS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`3 – Reviewed previously and no revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other (explain under "Comments")
`
` 2
`
` Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`Page 6 of 14
`
`(b) (4)
`
`(b) (4)
`
`

`

`DOCUMENT
`Methods Validation Consult
`
`
`
`
`18. STATUS: See below
`ONDC:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Biometrics
`EES
`Pharm/Tox
`
`RECOMMENDATION
`
`NA
`Acceptable
`Safe (Volatile and semi-
`volatile leachable)
`NA
`NA
`Acceptable
`Acceptable (Name)
`Acceptable
`(not a consult from
`CMC)
`
`DATE
`
`REVIEWER
`
`
`1/26/09
`6/29/09
`
`
`
`9/1/09
`2/5/09
`7/8/09
`6/17/09
`
`
`S.Fergusion (Report attached)
`Theresa Allio
`
`
`
`B.J.Westenberger/Pagay
`Raichell Brown
`S.Pagay for Catagorical Exemption
`Metcalfe
`
`DATE
`
`REVIEWER
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`B. Other Documents: None
`
`APPLICATION NUMBER
`This application
`
`
`
`
`9/1/09
`
`
`
`
`DESCRIPTION
`
`Biopharm
`LNC
`Methods Validation
`OPDRA (DMEPA)
`EA
`Microbiology
`
`
`OGD: NA
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Microbiology
`EES
`Methods Validation
`Labeling
`Bioequivalence
`EA
`Radiopharmaceutical
`
`19. ORDER OF REVIEW (OGD Only)
`
`
`RECOMMENDATION
`
`
`
`
`
`
`
`
`
`The application submission(s) covered by this review was taken in the date order of
`receipt. ____ Yes ____ No If no, explain reason(s) below:
`
`
`
`Page 7 of 14
`
`

`

`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`The Chemistry Review for NDA 22-288
`
`The Executive Summary
`
` I. Recommendations
`
`
`
`
`A. Recommendation and Conclusion on Approvability
`From the chemistry, manufacturing and controls standpoint, the NDA is recommended for
`approval. Methods Validation studies from the FDA laboratory are completed and the methods
`are acceptable.
`
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable - NA
`
`
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Substance
`Bepotastine besilate is manufactured by Ube Industries and the information for the
`NDA is submitted through DMF #19966. Bepotastine besilate is a white crystalline
`powder with no odor and bitter taste. It is very soluble in
` but sparingly
`soluble in
`. It is stable when exposed to light, and optically active.
`The S-isomer is the active drug and
` is controlled as an impurity through
`synthesis. The distribution coefficient in 1-octanol is higher than in aqueous buffer in
`the pH 5-9 range. There are 10 potential impurities but only one impurity is above
`0.1%. Two potential genotoxic impurities
`
`. Residual
` are controlled below
` is controlled below
` Bepotastine besilate is stable under long term storage conditions for (25ºC/60%
`RH) over 5 years.
`
`Drug Product
`
`Bepotastine besilate was originally developed as an oral tablet dosage form and got
`approval in Japan in 2000 for allergic rhinitis. It is a non-sedating anti-allergic drug.
`The proposed NDA is an ophthalmic solution indicated for allergic conjunctivitis.
`Bepotastine besilate ophthalmic solution 1.5% is a sterile solution. It is an aqueous
`solution to be administered as drops at or near physiological pH range of tears. The
`formulation contains sodium chloride, monobasic sodium phosphate as dihydrate,
`benzalkonium chloride, sodium hydroxide and purified water; typically these
`components are used for
`, preservative action, pH adjustment,
`
`Page 8 of 14
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`buffering capacity and a vehicle for administration, respectively. It was demonstrated
`during the formulation development that sodium chloride
`
` All excipients are of
`
`
`
`USP/NF grade. It is manufactured as a
`
` solution.
`
`
`
`
`
`
`
` The fill volumes are 1,
`2.5, 5, and 10 mL. The release and stability testing includes all the typical tests for
`sterile ophthalmic solutions (description, assay, impurities, pH, osmolality, particulate
`matter, preservative assay, microbiological testing). Also, a one time testing included
`the following studies: freeze-thaw, weight gain/loss due to water vapor transmission
`from the container, semi-volatile and volatile leachable material released into the
`ophthalmic solution from the container and label. Stability data on 23 batches
`manufactured for clinical, non-clinical and registration studies (Primary and support
`batch data) supports 12 months shelf life for the 1 mL fill and 18 months for the 2.5, 5
`and 10 mL fill sizes.
`
`B. Description of How the Drug Product is Intended to be Used
`The drug product is a sterile solution and should be dispensed in its original container.
`The label should indicate that the solution is for topical use only and not for injection or
`oral use. Also, the label should indicate to not touch dropper tip to any surface as it may
`contaminate the contents. The usual dose is to instill one drop in the affected eye twice
`a day. The product is stored under ambient conditions (15ºC to 30ºC) and discarded as
`indicated on the manufacturer’s label at expiration date.
`
`C. Basis for Approvability or Not-Approval Recommendation
`The following items are satisfactorily completed for approvability consideration:
`DMF for the drug substance is adequate.
`All manufacturing, testing and packaging facilities for the drug substance and the drug
`product received acceptable status from compliance ((EER attached to Review 1)
`The drug substance and drug product quality is reproducible based on the batch analysis
`data for release and stability.
`Manufacturing processes for the drug substance and the drug product are well
`controlled.
`ISTA has provided satisfactory response to all deficiencies.
`FDA laboratory conducted
` and the proposed methods for assay and impurities are
`acceptable.
`
`
`
`III. Administrative
`
`
`A. Reviewer’s Signature
`
`
`Page 9 of 14
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`
`
`
`B. Endorsement Block
`
`
`
`Chemist Name/Date: Same date as draft review
`ChemistryTeamLeaderName/Date
`ProjectManagerName/Date
`
`
`C. CC Block
`
`Page 10 of 14
`
`4 Page(s) have been Withheld in Full following this page as B4 (TS)
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22288
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`ISTA
`PHARMACEUTICA
`LS
`
`------------------------------------------
`BEPOTASTINE BESILATE
`OPHTHALMIC SOLUTION
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHRIKANT N PAGAY
`09/15/2009
`
`NORMAN R SCHMUFF
`09/22/2009
`
`

`

`MEMORANDUM
`
`
`Date: August 13, 2009
`To:
`NDA 22-288
`
`From: Elaine Morefield, Ph.D.
`
`Division Director
`
`Pre-marketing Assessment Division II
`
`ONDQA
`
`Subject: Tertiary review of ONDQA recommendation for NDA 22-288, Bepreve (bepoststine
`besilate ophthalmic Solution) 1.5%.
`
` I
`
` have assessed the ONDQA reviews of NDA 22-288, Bepreve (bepoststine besilate ophthalmic
`Solution) 1.5%. The sponsor has submitted data assuring that they can produce a quality product.
`Therefore, I concur with the ONDQA recommendation of approval from the CMC perspective.
`
`

`

`Linked Applications Submission
`Type/Number
`--------------------
`--------------------
`NDA 22288
`ORIG 1
`
`Sponsor Name
`
`Drug Name / Subject
`
`--------------------
`
`------------------------------------------
`BEPOTASTINE BESILATE
`OPHTHALMIC SOLUTION
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELAINE M MOREFIELD
`08/13/2009
`
`

`

`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`NDA 22-288
`
`Bepotastine Besilate 1.5% Ophthalmic Solution
`
`
`ISTA Pharmaceuticals, Inc.
`
`
`
`Shrikant Pagay
`ONDQA/OPS/DAIOP
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`I. 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 Chemistry 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..........................................................9
`C. Basis for Approvability or Not-Approval Recommendation............................................................9
`
`III. Administrative...........................................................................................................................9
`A. Reviewer’s Signature........................................................................................................................9
`B. Endorsement Block.........................................................................................................................10
`C. CC Block ........................................................................................................................................10
`
`Chemistry Assessment.......................................................................................... 11
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`Chemistry Review Data Sheet
`
`
`
`
`1. NDA #22-288
`
`
`2. REVIEW #: 2
`
`
`3. REVIEW DATE: 6-May-2009
`
`
`4. REVIEWER: Shrikant Pagay
`
`
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`IND 66,864/ Original
`Amendment
`
`
`
`
`
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`Original NDA
`Amendment
`Amendment
`Amendment
`Amendment
`
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`Document Date
`12/20/06/
`9/10/08
`
`Document Date
` 11/12/08
`12/10/08
`7/2/09
`7/8/09
`7/31/09
`
`
`Name:
`
`ISTA Pharmaceuticals Inc
`
`Page 3 of 23
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Address:
`
`15295 Alton Parkway, Irvine, CA 92618
`
`Representative:
`
`Paul Nowacki, Director, regulatory Affairs
`
`Telephone:
`
`949-789-3109
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`a) Proprietary Name: Bepreve
`b) Non-Proprietary Name (USAN): Bepotastine Besilate
`c) Code Name/# (ONDC only):TAU-284; SNJ-1773
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 1
`• Submission Priority: S
`
`
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b) (1)
`
`
`10. PHARMACOL. CATEGORY: Allergic Conjunctivitis
`
`
`11. DOSAGE FORM: Solution
`
`
`12. STRENGTH/POTENCY: 1.5% by weight
`
`
`
`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
`
`Page 4 of 23
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`Proposed Name:
`
`USAN Name: (+) -4-[[(S) p-Chloro-alpha -2-pyridylbenzyl] oxy]-1-piperidine
`butyric acid monobenzenesulfonate
`
`
`
`
`
`
`
`S
`
`
`
`H
`25
`
`ClN
`2
`
`O
`3
`
`•C
`6
`
`H
`6
`
`O
`3
`
`21
`
` C
`
`
`MW: 547.06
`
`Free acid Bepotastine MW. 388.90
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`Page 5 of 23
`
`

`

`
`
`
`
`
`A. DMFs:
`
`
`
`
`
`TYPE HOLDER
`
`Ube
`Industries
`Ltd.
`
`II
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`DMF
`#
`19966
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`ITEM
`REFERENCED
`Bepotastine
`besilate
`
`CODE1
`
`STATUS2
`
`1
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`Adequate
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`DATE
`REVIEW
`COMPLETED
`4/4/09
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`COMMENTS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`3 – Reviewed previously and no revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other (explain under "Comments")
`
` 2
`
` Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`Page 6 of 23
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`18. STATUS: See below
`ONDC:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Biometrics
`EES
`Pharm/Tox
`
`RECOMMENDATION
`
`NA
`Acceptable
`Safe (Volatile and semi-
`volatile leachable)
`NA
`NA
`Pending response
`Accptable (Name)
`Acceptable
`(not a consult from
`CMC)
`
`DATE
`
`REVIEWER
`
`
`1/26/09
`6/29/09
`
`
`
`
`2/5/09
`7/8/09
`6/17/09
`
`
`S.Fergusion (Report attached)
`Theresa Allio
`
`
`
`Requested 7/28/09
`Raichell Brown
`S.Pagay for Catagorical Exemption
`Metcalfe
`
`DATE
`
`REVIEWER
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`B. Other Documents: None
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`
`
`
`
`
`DESCRIPTION
`
`
`
`
`
`
`Biopharm
`LNC
`Methods Validation
`OPDRA (DMEPA)
`EA
`Microbiology
`
`
`OGD: NA
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Microbiology
`EES
`Methods Validation
`Labeling
`Bioequivalence
`EA
`Radiopharmaceutical
`
`19. ORDER OF REVIEW (OGD Only)
`
`
`RECOMMENDATION
`
`
`
`
`
`
`
`
`
`The application submission(s) covered by this review was taken in the date order of
`receipt. ____ Yes ____ No If no, explain reason(s) below:
`
`
`
`Page 7 of 23
`
`

`

`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`The Chemistry Review for NDA 22-288
`
`The Executive Summary
`
` I. Recommendations
`
`
`
`
`A. Recommendation and Conclusion on Approvability
`From the chemistry, manufacturing and controls standpoint, the NDA is recommended for
`approval. Methods Validation results from the FDA laboratory are pending, but this is not an
`approvability issue.
`
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable - NA
`
`
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Substance
`Bepotastine besilate is manufactured by Ube Industries and the information for the
`NDA is submitted through DMF #19966. Bepotastine besilate is a white crystalline
`powder with no odor and bitter taste. It is very soluble in
` but sparingly
`soluble in
`. It is stable when exposed to light, and optically active.
`The S-isomer is the active drug and
` is controlled as an impurity through
`synthesis. The distribution coefficient in 1-octanol is higher than in aqueous buffer in
`the pH 5-9 range. There are 10 potential impurities but only one impurity is above
`0.1%. Two potential genotoxic impurities
`
` Residual
` are controlled below
` is controlled below
` Bepotastine besilate is stable under long term storage conditions for (25ºC/60%
`RH) over 5 years.
`
`Drug Product
`
`Bepotastine besilate was originally developed as an oral tablet dosage form and got
`approval in Japan in 2000 for allergic rhinitis. It is a non-sedating anti-allergic drug.
`The proposed NDA is an ophthalmic solution indicated for allergic conjunctivitis.
`Bepotastine besilate ophthalmic solution 1.5% is a sterile solution. It is an aqueous
`solution to be administered as drops at or near physiological pH range of tears. The
`formulation contains sodium chloride, monobasic sodium phosphate as dihydrate,
`benzalkonium chloride, sodium hydroxide and purified water; typically these
`components are used for
`, preservative action, pH adjustment,
`
`Page 8 of 23
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`buffering capacity and a vehicle for administration, respectively. It was demonstrated
`during the formulation development that sodium chloride
`
` All excipients are of
`
`
`
`USP/NF grade. It is manufactured as a
`
` solution.
`
`
`
`
`
`
`
` The fill volumes are 1,
`2.5, 5, and 10 mL. The release and stability testing includes all the typical tests for
`sterile ophthalmic solutions (description, assay, impurities, pH, osmolality, particulate
`matter, preservative assay, microbiological testing). Also, a one time testing included
`the following studies: freeze-thaw, weight gain/loss due to water vapor transmission
`from the container, semi-volatile and volatile leachable material released into the
`ophthalmic solution from the container and label. Stability data on 23 batches
`manufactured for clinical, non-clinical and registration studies (Primary and support
`batch data) supports 12 months shelf life for the 1 mL fill and 18 months for the 2.5, 5
`and 10 mL fill sizes.
`
`B. Description of How the Drug Product is Intended to be Used
`The drug product is a sterile solution and should be dispensed in its original container.
`The label should indicate that the solution is for topical use only and not for injection or
`oral use. Also, the label should indicate to not touch dropper tip to any surface as it may
`contaminate the contents. The usual dose is to instill one drop in the affected eye twice
`a day. The product is stored under ambient conditions (15ºC to 30ºC) and discarded as
`indicated on the manufacturer’s label at expiration date.
`
`C. Basis for Approvability or Not-Approval Recommendation
`The following items are satisfactorily completed for approvability consideration:
`DMF for the drug substance is adequate.
`All manufacturing, testing and packaging facilities for the drug substance and the drug
`product received acceptable status for compliance ((EER attached to Review 1)
`The drug substance and drug product quality is reproducible based on the batch analysis
`data for release and stability.
`Manufacturing processes for the drug substance and the drug product are well
`controlled.
`ISTA has provided satisfactory response to all deficiencies. However, results from FDA
`laboratory for
` are pending.
`
`
`
`III. Administrative
`
`
`A. Reviewer’s Signature
`
`
`
`Page 9 of 23
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`CHEMISTRY REVIEW TEMPLATE
`
`Chemistry Assessment Section
`
`
`
`B. Endorsement Block
`
`
`
`Chemist Name/Date: Same date as draft review
`ChemistryTeamLeaderName/Date
`ProjectManagerName/Date
`
`
`C. CC Block
`
`Page 10 of 23
`
`13 Page(s) have been Withheld in Full following this page as B4 (TS)
`
`

`

`Linked Applications Submission
`Type/Number
`--------------------
`--------------------
`NDA 22288
`ORIG 1
`
`NDA 22288
`
`NDA 22288
`
`ORIG 1
`
`ORIG 1
`
`Sponsor Name
`
`Drug Name / Subject
`
`--------------------
`
`------------------------------------------
`BEPOTASTINE BESILATE
`OPHTHALMIC SOLUTION
`BEPOTASTINE BESILATE
`OPHTHALMIC SOLUTION
`BEPOTASTINE BESILATE
`OPHTHALMIC SOLUTION
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHRIKANT N PAGAY
`08/06/2009
`
`NORMAN R SCHMUFF
`08/09/2009
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 22-288
`
`Bepotastine Besilate 1.5% Ophthalmic Solution
`
`
`ISTA Pharmaceuticals, Inc.
`
`
`
`Shrikant Pagay
`ONDQA/OPS/DAIOP
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`I. 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 Chemistry 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..........................................................9
`C. Basis for Approvability or Not-Approval Recommendation............................................................9
`
`III. Administrative...........................................................................................................................9
`A. Reviewer’s Signature........................................................................................................................9
`B. Endorsement Block...........................................................................................................................9
`C. CC Block ........................................................................................................................................10
`
`Chemistry Assessment.......................................................................................... 11
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.......11
`S
` DRUG SUBSTANCE [Bepotastine, ISTA]..................................................................................11
`P
` DRUG PRODUCT [Bepotastine, ISTA] ......................................................................................20
`A
` APPENDICES ..............................................................................................................................69
`R REGIONAL INFORMATION .....................................................................................................69
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ..................................70
`A. Labeling & Package Insert ............................................................................................................70
`B. Environmental Assessment Or Claim Of Categorical Exclusion ...................................................73
`
`III. List Of Deficiencies To Be Communicated.......................................................................74
`
`
`
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`Chemistry Review Data Sheet
`
`
`
`
`1. NDA #22-288
`
`
`2. REVIEW #:1
`
`
`3. REVIEW DATE: 6-May-2009
`
`
`4. REVIEWER: Shrikant Pagay
`
`
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`IND 66,864/ Original
`Amendment
`
`
`
`
`
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`
`Original NDA
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`Document Date
`12/20/06/
`9/10/08
`
`Document Date
` 11/12/08
`
`Name:
`
`Address:
`
`ISTA Pharmaceuticals Inc
`
`15295 Alton Parkway, Irvine, CA 92618
`
`Representative:
`
`Paul Nowacki, Director, regulatory Affairs
`
`Telephone:
`
`949-789-3109
`
`Page 3 of 77
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`a) Proprietary Name: Bepreve
`b) Non-Proprietary Name (USAN): Bepotastine Besilate
`c) Code Name/# (ONDC only):TAU-284; SNJ-1773
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 1
`• Submission Priority: S
`
`
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b) (1)
`
`
`10. PHARMACOL. CATEGORY: Allergic Conjunctivitis
`
`
`11. DOSAGE FORM: Solution
`
`
`12. STRENGTH/POTENCY: 1.5% by weight
`
`
`
`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
`
`
`
`
`
`
`
`Page 4 of 77
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`Proposed Name:
`
`USAN Name: (+) -4-[[(S) p-Chloro-alpha -2-pyridylbenzyl] oxy]-1-piperidine
`butyric acid monobenzenesulfonate
`
`
`
`
`
`
`
`S
`
`
`
`H
`25
`
`ClN
`2
`
`O
`3
`
`•C
`6
`
`H
`6
`
`O
`3
`
`21
`
` C
`
`
`MW: 547
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`Page 5 of 77
`
`

`

`
`
`
`
`
`A. DMFs:
`
`
`
`
`
`TYPE HOLDER
`
`Ube
`Industries
`Ltd.
`
`II
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`DMF
`#
`19966
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`ITEM
`REFERENCED
`Bepotastine
`besilate
`
`CODE1
`
`STATUS2
`
`1
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`4
`
`Adequate
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`DATE
`REVIEW
`COMPLETED
`4/4/09
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`COMMENTS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`3 – Reviewed previously and no revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other (explain under "Comments")
`
` 2
`
` Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`Page 6 of 77
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`18. STATUS: See below
`ONDC:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Biometrics
`EES
`Pharm/Tox
`
`RECOMMENDATION
`
`NA
`Acceptable
`Safe (Volatile and semi-
`volatile leachables)
`NA
`NA
`Pending response
`Approved (Name)
`Pending response
`(not a consult from
`CMC)
`
`DATE
`
`REVIEWER
`
`
`1/26/09
`6/29/09
`
`
`
`
`2/5/09
`
`6/17/09
`
`
`S.Fergusion (Report attached)
`Theresa Allio
`
`
`
`
`Raichell Brown
`
`Metcalfe
`
`DATE
`
`REVIEWER
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`