CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203168Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`To: NDA 203168 File
`
`Date: O5-April-2013
`
`From: Rapti D. Madurawe, Ph.D., Branch Chief, Branch V/Division II, ONDQA
`
`Dr. Rao Kambhampati recommended CMC labeling revisions in Addendum1 to Review #1 dated
`04-April-2013. The recommended labeling changes may be made post-approval and the NDA
`may be approved with the current labeling provided in Amendment 0012 dated 03-April-2013.
`
`Reference ID: 3288889
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`RAPTI D MADURAWE
`04/05/2013
`
`Reference ID: 3288889
`
`

`

`NDA# 203168
`Addendum 1 to Quality Review #1
`For Division of Topical and Ophthalmology Products
`
`1. NDA# 203168
`
`2. Amendment # and Date: 0011 dated 3/18/13
`
`3. REVIEW DATE: 4-4-13
`
`4. REVIEWER: Rao V. Kambhampati, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`Previous Documents
`N203168 ORIG-1 0000 (0) Quality Review
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Document Date
`2/25/13
`
`Submissions Reviewed
`NDA 203-168 Amendment 0011 (11)
`
`Global Submit Date
`3/18/13
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`Name:
`
`Address:
`
`Representative:
`
`Bausch & Lomb Incorporated (formerly ISTA
`Pharmaceuticals, Inc.)
`50 Technology Drive
`Irvine, CA 92618
`N/A
`
`Telephone:
`
`949-727-0833
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: ProlensaTM
`b) Non-Proprietary Name (USAN): Bromfenac ophthalmic solution, 0.07%
`c) Code Name/# (ONDQA only): N/A
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 5
`• Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: NDA (CDA, 21 CFR 314.50), 505 (b)(1)
`
`Reference ID: 3287796
`
`

`

`10. PHARMACOL CATEGORY: Nonsteroidal anti-inflammatory drug (NSAID)
`for ophthalmic use (Cyclooxygenase 1 and 2
`inhibitor)
`
`11. DOSAGE FORM:
`
` Ophthalmic solution
`
`12. STRENGTH/POTENCY: 0.07%
`
`13. ROUTE OF ADMINISTRATION: Topical (ocular) instillation
`
`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:
`Sodium [2-amino-3-(4-bromobenzoyl) phenyl] acetate sesquihydrate
`or
`Benzeneacetic acid, 2-amino-3-(4-bromobenzoyl)-, monosodium salt, sesquihydrate
`
`C15H11 BrNNaO3 • 1½ H2O
`383.17
`USAN Name: Bromfenac sodium
`
`Reference ID: 3287796
`
`2
`
`

`

`Review
`
`The Quality (CMC) review ofthis NDA# 203-168 wasfiled in DARRTS on 2/26/13. On 3/18/13,
`the applicant submitted an amendment #0011 (11) in response to the DTOP ’s e-mail
`communication dated 3/15/13 regarding labeling and labels. This addendum includes the quality
`review ofthe amendment #11.
`
`Package Inselt: The changes below (indicated in red) are recommended to the draftpackage
`insert that was submitted in amendment #11. The recommended changes show the active as a
`sesquihydrate
`”m
`
`11 DESCRIPTION
`
`PROLENSA (bromfenac ophthahnic solution) 0.07% is a sterile, topical, nonsteroidal anti-
`inflammatory drug (NSAID) for ophthalmic use. Each mL of PROLENSA contains 0.805
`mg bromfenac sodium sesquihydrate (equivalent to 0.7 mg bromfenac free acid). Bromfenac
`sodium is designated chemically as sodium [2-amino-3-(4-bromobenzoyl) phenyl] acetate
`
`sesquihydrate, with an empirical formula of C15H11BrNNa03O l‘/2H20. The chemical
`stiucture for bromfenac sodium
`M“) is:
`
`HzN
`
`CHzcozm - 11/2H20
`
`Bromfenac sodium is a yellow to orange crystalline powder. The molecular weight of
`bromfenac sodium is 383.17. PROLENSA ophthahnic solution is supplied as a sterile
`aqueous 0.07% solution, with a pH of 7.8. The osmolality of PROLENSA ophthahnic
`solution is approximately 300 mOsmol/kg.
`
`Each mL of PROLENSA ophthalmic solution contains:
`Active: bromfenac sodium
`(m4) sesquihydrate
`mm bromfenac free acid.
`
`mm which is equivalent to
`
`”(000094:
`Preservative: benzalkonium chloride
`Inactives: boric acid, edetate disodium, povidone, sodilim borate, sodium sulfite, tyloxapol,
`sodium hydroxide to adjust pH and water for injection, USP.
`
`Container and Carton Labels: The applicant submitted the following revised labels for the
`packaging configurations indicated in the Table 1 below:
`
`Reference ID: 3287796
`
`

`

`Tabb 1. Draft Iabeiag Coupe-eats for PROM-INSA" (bro-mac
`
`ophthal-ie solution) 0.07%
`
`0.6 mL Fromm Sample
`
`0-5 IL Sample Bottle Label
`
`NDC No. 2420860106
`
`0.6 “.1, 3““, Cum
`
`0.8 mL momma: Sample
`
`0-8 IL Sample Bottle Label
`
`NDCNo. 24208-601—08
`
`03 mL Sal-pk Cm”
`
`3ILSampleCarton
`
`15 mL Trade
`
`1.6 IL Sample Bottle Label
`
`NDCNo. 24208-601-01
`
`l6 “IL Sa-ple Carton
`
`
`
`_mLTad:_N°”ML”
`
`3ILSampleBottleLabel
`
`Reference ID: 3287796
`
`
`
`

`

`Comments: The above revised draft labels contain all the required CMC related information
`except the carton labels do not contain equivalency statement for the active ingredient.
`Presently, the statement reads as follows: “Each mL of Prolensa ophthalmic solution contains:
`Active: bromfenac sodium hydrate 0.805 mg”. Preservative: benzalkonium chloride (0.005%)
`……….. In this statement active is given in mg, active name includes “hydrate”, no equivalency
`statement, and benzalkonium chloride is given in %. Preservative is identified separately.
`
`Reference ID: 3287796
`
`11
`
`(b) (4)
`
`

`

`, the same a Iicant
`
`To a related NDA# 21-664
`Lamb submitted
`
`
`
`Reference ID: 3287796
`
`

`

`ForNDA203—168CartonLabels: “EachmLoiProlensamoihthalmicsolutioncontains:
`
`Conclusion and Recommendation: We recommend the above changes to the draftpackage
`insert and carton labels.
`
`Primary Reviewer: Rao V. Kambhampati, Ph.D.
`
`Secondary Reviewer: Rapti Madurawe, Ph.D.
`
`Reference ID: 3287796
`
`13
`
`

`

`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`RAO V KAMBHAM PATI
`
`04/04/2013
`
`RAPTl D MADURAWE
`
`04/04/2013
`
`Reference ID: 3297113
`Reference ID: 3297118
`Reference lD'. 32877 6
`
`

`

` CHEMISTRY REVIEW
`
`NDA 203168
`
`ProlensaTM (bromfenac ophthalmic solution) 0.07%
`
`Applicant: ISTA Pharmaceuticals, Inc.
`
`Quality (CMC) Review #1
`
`Rao V. Kambhampati, Ph.D.
`
`For Division of Transplant and Ophthalmology Products
`(DTOP)
`
`Reference ID: 3267244
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`1. Recommendations ...................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements, and/or Risk
`Management Steps, if Approvable ................................................................................................... 7
`
`II. Summary of Chemistry Assessments.........................................................................................7
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 7
`
`B. Description of How the Drug Product is Intended to be Used.......................................................... 9
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 9
`
`III. Administrative ......................................................................................................................... 10
`
`A. Reviewer’s Signature ...................................................................................................................... 10
`
`B. Endorsement Block ......................................................................................................................... 10
`
`C. CC Block ........................................................................................................................................ 10
`
`Chemistry Assessment ........................................................................................... l 1
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ....... 11
`
`S DRUG SUBSTANCE ................................................................................................................... 11
`
`P DRUG PRODUCT [Bromfenac Ophthahnic Solution, 0.07% ..................................................... 21
`
`A APPENDICES .............................................................................................................................. 90
`
`R REGIONAL INFORMATION ..................................................................................................... 91
`
`II. Review Of Common Technical Document-Quality (Ctd—Q) Module 1 ..................................94
`
`A. Labeling & Package Insert ............................................................................................................ 94
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................. 102
`
`III.
`
`List Of Deficiencies To Be Communicated ..................................................................... 103
`
`Reference ID: 3267244
`
`

`

`
`
`Chemistry Review Data Sheet
`
`NDA 203168
`
`Chemistry Review Data Sheet
`
`1. NDA# 203168
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 2—25—13
`
`4. REVIEWER: Rao V. Kambhampati, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`None
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissions Reviewed
`
`N203168 ORIG—l 0000 (0)
`Amendment 0001 (1)
`Amendment 0002 (2)
`Amendment 007 (7)
`Amendment 008 (8)
`Amendment 009 (9)
`
`M. NAME & ADDRESS OF APPLICANT:
`
`Global Submit Date
`
`6/7/2012
`
`8/21/12
`
`8/31/12
`
`11/19/12
`12/19/12
`
`12/21/12
`
`Name:
`
`Address:
`
`Bausch & Lomb Incorporated (formerly ISTA
`Pharmaceuticals, Inc.)
`50 Technology Drive
`Irvine, CA 92618
`
`Representative:
`
`N/A
`
`Telephone :
`
`949-727-0833
`
`M. DRUG PRODUCT NANHE/CODE/TYPE:
`
`Reference ID: 3267244
`
`Page 3 of 106
`
`

`

`
`
`Chemistry Review Data Sheet
`a) Proprietary Name: ProlensaTM
`b) Non-Proprietary Name (USAN): Bromfenac ophthalmic solution, 0.07%
`c) Code Name/# (ONDQA only): N/A
`d) Chem. Type/Submission Priority (ONDC only):
`
`NDA 203168
`
`0 Chem. Type: 5
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: NDA (CDA, 21 CFR 314.50), 505 (b)(1)
`
`10. PHARMACOL CATEGORY: Nonsteroidal anti-inflammatory drug (NSAID)
`for ophthalmic use (Cyclooxygenase l and 2
`inhibitor)
`
`11. DOSAGE FORM:
`
`Ophthalmic solution
`
`12. STRENGTH/POTENCY: 0.07%
`
`13. ROUTE OF ADMINISTRATION: Topical (ocular) instillation
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS [SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM 1:
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`2-Amino-3-benzoylbenzeneacetamide
`or
`
`2-(2-Amino-3-benzoylphenyl)acetamide
`
`C15H11BrNN303 ° 1% H20
`383.17
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`M. DIVIFs:
`
`T
`
`ITEM
`
`YP HOLDER
`E
`
`REFEREN CODEl STATUS2
`CED
`
`DATE
`
`REVIEW
`
`COMPLETED Senju
`
`Bromfenac
`
`10/26/04 and
`
`Reference ID: 3267244
`
`Page 4 of 106
`
`

`

`CHEMISTRY REVIEW
`
`Chemis Review Data Sheet
`
`NDA 203168
`
`(Produced by
`Regis
`Technologies
`
`Adequate
`
` 11/26/12
`
`Adequate
`
`10/24/ 12
`
`Adequate
`
`12/19/12
`
`Adequate
`
`11/14/12
`
`Adequate
`
`1/26/07
`
`Adequate
`
`11/14/12
`
`Adequate
`
`8/31/07
`
`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”)
`
`Reference ID: 3267244
`
`Page 5 of 106
`
`

`

` '"fl‘t
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`NDA 203168
`
`2Adequate. 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
`
`”m“ ”“3”“ 5“”
`Pfizer Inc., agent for Wyeth
`Pharmaceuticals
`
`Bromfenac (Sodium) Ophthalmic
`Solution(s)
`
`Bromfenac Ophthahnic Solution
`0.09%. Al troved
`
`
`
`
`M. STATUS:
`
`ONDC:
`
`CONSULTS/ CMC
`
`RELATED
`
`REVIEWS
`
`RECOMNIENDATION
`
`DATE
`
`LNC 0ND O A
`
`Not a 1 licable
`
`Methods Validation
`
`Not a o licable
`
`OMEPR
`
`Proprietary name
`acceptable (review in
`DARRTS
`
`7/27/12
`
`2/20/13
`
`2/20/13
`
`11/7/12
`
`A- Alexandrow I D-001
`
`Rao Kambham n ati, Ph.D.
`
`Rao Kambhamati, Ph.D.
`
`Jung Lee, RPh.
`
`Product Quality
`Microbiolo 3
`
`Accetable
`
`Acceptable
`
`1/30/13
`
`1/22/13
`
`Rao Kambha .. ati, PhD
`
`Stephene E. Langille, Ph.D.
`
`19. ORDER OF REVIEW (OGD Only): N/A
`
`The application submission(s) covered by this review was taken in the date order of
`receipt.
`Yes
`No
`Ifno, explain reason(s) below:
`
`Reference ID: 3267244
`
`Page 6 of 106
`
`

`

`
`
`Executive Summary Section
`NDA 203168
`The Chemistry Review for NDA 203168
`
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`This NDA has provided sufficient information to assure the identity, strength, purity,
`and quality of the drug product. The labels have adequate CMC information as
`required. The tradename, ProlensaTM, for the drug product is acceptable. The
`establishment evaluation of the manufacturing and testing facilities was complete and
`the Office of Compliance issued an Overall Acceptable Recommendation for this NDA.
`From the CMC perspective, this NDA is recommended for approval.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`Not applicable.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Substance:
`The Active Pharmaceutical Ingredient (API) in the drug product is bromfenac sodium
`drug substance. The same drug substance is used in the manufacture of the currently
`marketed bromfenac ophthalmic solution 0.09% formulation in this applicant’s original
`NDA 21-664, which was approved on 24 March 2005. The manufacturer and supplier,
`manufacturing process, test methods, specifications, and all other parameters are the
`same as those applied to the drug substance for the currently approved
`XibromTM/BromdayTM 0.09% formulation. Bausch & Lomb (formerly ISTA
`Pharmaceuticals', Inc.; ISTA) makes reference to Senju’s Type II Drug Master File
`ODMF) 16414 for pertinent information required for drug substance and a Letter of
`Authorization was provided from Senju. The original DlVIF was reviewed by Yong-de
`Lu (ONDQA) on 10/ 16/04, who found it to be adequate and the subsequent Annual
`Reports (1 to 10) were reviewed by this reviewer. The DMF is again found to be
`adequate and a Chemistry Review #2 (February 2013) was filed in DARRTS.
`
`Drug Product:
`The drug product is a non-steroidal anti—inflammatory drug (NSAID) for topical
`ophthalmic use. It is supplied as a clear, yellow, sterile solution containing 0.07%
`bromfenac free acid and dispensed from a 7.5cc capacity white low density
`polyethylene @DPE) bottle with a white linear m4) tip, and grey
`screw cap. The proposed trade sizes for the drug product are 1.6 mL and 3 mL per
`bottle. In addition, the applicant proposed sample sizes of 0.6 mL and 0.8 mL per
`bottle.
`
`0’) (4)
`
`Reference ID: 3267244
`
`Page 7 of 106
`
`

`

`
`
`Executive Summary Section
`
`NDA 203168
`
`Each 1 mL of the drug product contains 0.085 mg of bromfenac sodium sesquihydrate
`(equivalent to 0.07% of free acid form) as the active in edient and the followin
`excipients: boric acid
`and sodium borate
`
`
`
`sodium sulfite
`and pov1 one
`
`
`edetate disodium
`benzalkonium chloride
`
`
`
`preservative; and so um y 0x1 e 1 necessary to adjust pH to 7.8).
`
`The components of the container closure system used for bromfenac ophthalmic
`solution 0.07% are identical to the marketed bromfenac ophthalmic solution 0.09%.
`
`controlled dro
`
`er ti
`
`is then inserted.
`
`
`filled into 7.5 cc size*- round bottles mto w c a
`Bromfenac ophthalmic solution, 0.07%is
`
`
`screw-ongrafi cap. A
`
`
`
`
`tamper-evident
`
`
`neck of the bottle.
`
`is shrink-seale over
`
`e cap and the
`
`The drug product1s manufactured by Bausch & Lomb Pharmaceuticals, Inc. (B&L in
`Tam a, FL. The manufacturin
`
`
`
`The revised specification for the drug product included appearance of solution,
`description of container, identification (UV and HPLC , bromfenac sodium assay
`(HPLC; 90-110%), bromfenac '
`urities (total),
`any individual
`specified impurity (excluding
`), any individual unspecified impurity, pH,
`osmolality, benzalkonium chloride, EDTA, sodium sulfite, sterility, bacterial
`endotoxins, particulate matter, weight loss. In the initial specification, the applicant did
`not include tests for sodium sulfite and weight loss.
`
`B&L tests the incoming raw materials and, produces and tests the final product (release
`and ongoing stability). Container closure system was tested per USP <661> and <87>.
`In addition, drug product filled container closure systems were tested for
`leachable/extractable levels and studies are ongoing through end of shelf life. A safety
`
`Reference ID: 3267244
`
`Page 8 of 106
`
`

`

`
`
`NDA 203168
`Executive Summary Section
`evaluation of these potential substances indicates the levels are below their safety
`threshold. The container closure system (bottle, dropper tip and cap) components aremm
`
`The container-closure system was shown to maintain
`the sterility of the finished product. Studies showed that the finished product is not
`adversely affected by light exposure or extreme temperatures.
`
`Bromfenac ophthahnic solution, 0.07% utilizes an
`
`com)
`
`The
`
`manufacturing process validation will be completed prior to commercialization. B&L
`will perform process validation on 3 consecutive commercial scale batches of
`bromfenac ophthalmic solution, 0.07%.
`
`Stability data are available for the 0.6 mL and 3 mL fill sizes. Although the stability of
`the 0.8 mL and 1.6 mL fill sizes were not directly investigated, these fill sizes are
`bracketed (based on ICH QlD) between two extreme fill sizes. The 0.8 mL fill is
`bracketed between the studied 0.6 mL and 1 mL configurations while the 1.6 mL fill is
`bracketed by the studied 1.5 mL and 3 mL configurations. Consequently, the proposed
`expiry for the 0.8 mL and 1.6 mL fill sizes will default to the most conservative of the
`bracketed extremes, which are the 0.6 mL and 3 mL fills, respectively. Based on 12
`months of real—time data, the expiration period granted is 12 months for the 0.8 and 0.6
`mL fill sizes. Based on 18 months of real-time data, the expiration dating period
`granted is 22 months for the 1.6 and 3 mL fill sizes. The recommended label storage
`condition is 15°C-25°C (59°F-77°F).
`
`B. Description of How the Drug Product is Intended to be Used
`PROLENSATM (bromfenac ophthahnic solution) 0.07% is supplied in a white LDPE
`plastic squeeze bottle with a 15 mm mmwhite dropper-tip and 15 mm
`mm
`gray cap as follows:
`
`0 1.6mL in a 7.5mL container (NDC 24208-602-01)
`
`. 3.0mL in a 7.5mL container (NDC 24208-602-03)
`One drop of PROLENSATM ophthahnic solution is applied to the affected eye once
`daily beginning 1 day prior to cataract surgery, continued on the day of surgery, and
`through the first 14 days of the postoperative period.
`
`In addition, Prolensa is supplied in sample size bottles (7.5 mL) containing 0.6 mL or
`0.8 mL solution.
`
`. Basis for Approvability or Not-Approval Recommendation
`The applicant resolved all the CMC related deficiencies that were communicated in the
`74-day and IR letter. The proposed formulation (0.07%) is a lower strength formulation
`of the currently approved formulation (0.09%) with some changes in the some of the
`excipients. The drug substance is manufactured and tested by the same facilities that are
`
`Reference ID: 3267244
`
`Page 9 of 106
`
`

`

`
`
`NDA 203168
`Executive Summary Section
`used for approved formulation. The applicant demonstrated that the drug product can be
`manufactured with consistent quality and purity by providing adequate batch analysis
`and including controls in the manufacturing and packaging operations. The
`specification for drug substance and drug product included all the tests that are required
`for a topical ophthahnic solution. Adequate stability data were provided for the drug
`substance and drug product. The product quality microbiology of this NDA was
`reviewed by the Microbiology Staff (OPS) reviewer and it was found to be acceptable
`after addressing all the deficiencies in the NDA. All the facilities involved in the
`manufacturing, testing, and packaging of the drug substance and drug product were
`found to be acceptable and an Overall Acceptable Recommendation for this NDA was
`issued by the Office of Compliance. The established name need not be reviewed
`because it is already marketed with the same name. The tradename, ProlensaTM, is
`acceptable from all the reviewers stand point as well as by the OMEPR (CDER).
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`Rao V. Kambhampati, Ph.D.
`
`B. Endorsement Block
`
`Primary Reviewer/Date: Rao V. Kambhampati, Ph.D.
`Secondary Reviewer/Date: Rapti Madurawe, PhD.
`
`C. CC Block
`
`96 Pages have been Wlfllheld in Full as b4 (CCIITS) immediately
`following this page.
`
`Reference ID: 3267244
`
`Page 10 of 106
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`RAO V KAMBHAMPATI
`02/26/2013
`
`RAPTI D MADURAWE
`02/26/2013
`
`Reference ID: 3267244
`
`

`

`Initial Quality Assessment Branch V
`Pre-Marketing Assessment Division II
`
` OND Division : Division of Transplant and Ophthalmology Products
` NDA : 203-168
` Applicant : ISTA
` Stamp Date : 07 June, 2012
` Proposed Trademark : Prolensa*
` Established Name : Bromfenac ophthalmic solution 0.07%
` Dosage Form : Ophthalmic solution
` Route of Administration : Topical
` Strength : 0.07%
` Indication: Treatment of inflammation and pain associated with
`cataract extraction
` Reviewer : Rao Kambhampati
`Quality Micro Reviewer: Steven Langille
` CMC Lead : Bala Shanmugam
`
` YES NO
`
`
`
`
` Acceptable for filing:
`Comments for 74-Day Letter:
`
`Summary and Critical Issues
`
`Summary
`
`Bromfenac ophthalmic solution 0.07% is administered once daily for the treatment of
`postoperative inflammation and reduction of ocular pain after cataract surgery. The NDA
`is filed as a 505 (b) (1). The submission is all electronic and located in the EDR (Link:
`\\CDSESUB1\EVSPROD\NDA203168\203168.enx)
`
`ISTA, the sponsor of the NDA under review is currently marketing a similar product,
`Bromday(cid:149) (bromfenac ophthalmic solution), 0.09% which was approved in 2010 (sNDA
`21664) which itself had a change in dosing regimen (QD) compared to the previously
`approved (March 2005) twice-a-day Xibrom(cid:149) product.
`
`In addition to the change in the concentration of bromfenac sodium, the current
`formulation has been slightly modified as compared to the approved product in that it
`replaces
` with tyloxapol. Bausch and Lomb, the manufacturer of the
`approved product will also manufacture the new formulation. The drug substance
`manufacturer also remains to be the same (Regis Technologies).
`
`* Based on initial evaluation, the proposed proprietary name was determined to be
`“conditionally acceptable” (Section 1.6.3, General Correspondence, Communication of
`May 14, 2012).
`
`Reference ID: 3164499
`
`(b) (4)
`
`

`

`IQA-NDA 203168
`
`Chemistry information for the drug substance, bromfenac sodium is referenced to DMF
`16414. A LOA from the DMF holder, Senju Pharmaceuticals is provided. Please note that
`Regis Technologies is the contract manufacturer of the drug substance.
`
`The drug product is formulated as a sterile ophthalmic solution for topical administration
`and the proposed commercial trade sizes are 1.6 mL and 3.0 mL in 7.5 mL LDPE bottle.
`Additionally, physician sample size of 0.6 mL and/or 0.8 mL in 7.5 mL LDPE bottle is
`also being proposed. Please note that bracketing approach has been used to support
`stability of the different fill volumes. The company is requesting a shelf-life of 12-months
`for the physician sample sizes and 22-months for the 1.6 mL and 3.0 mL commercial
`sizes when stored at 15-25(cid:113)C.
`
`Manufacturing and testing facilities have been entered in EES.
`
`The IND related to this submission is IND 060295. Please note that a pre-NDA meeting
`was held. The minutes of the Pre-NDA meeting is attached to this IQA for immediate
`reference.
`
`This NDA will be reviewed on a Standard time line.
`
`Important Timelines:
`
`(cid:120) Primary reviews - March 3, 2013
`(cid:120) Proposed labeling to applicant- target date- March 10, 2013
`(cid:120) CDTL review- March 17, 2013
`(cid:120) Circulate action package- March 17, 2013
`(cid:120) PDUFA – April 7, 2013
`
`Drug Substance
`
`All drug substance information related to manufacturing (contract manufactured by Regis
`Technologies) and controls is referenced to DMF 16414 (see table for status of this DMF
`at the time of this IQA). A letter of authorization from the DMF holder, Senju
`Pharmaceuticals has been provided.
`
`Reference ID: 3164499
`
`2
`
`

`

`-m .0.W“—Substance
`
`(Yes/No)
`
`IQA-NDA 203168
`
`
`
`sodium
`
`The last review is by
`Yong De Lu, dated
`October 26, 2004.
`
`There are several
`Annual Reports to be
`reviewed.
`
`0 As indicated above, Regis Technologies, Morton Grove, IL is the contract
`manufacturer for Senju Pharmaceuticals.
`
`0 The sponsor also references NDA 21-664 Wyeth) substance for the drug substance
`and has and provided a LOA from Pfizer (agent for Wyeth).
`0 Per company statement (Section 2.3.8.1), the manufacturing process, controls,
`specifications etc are the same as those for the drug substance for the currently
`approved.
`
`Drug Product
`
`The product is formulated as a sterile, preserved ophthahnic solution.
`. The drug product is manufactured by Bausch and Lomb, Inc., Tampa FL.
`. All excipients used in the formulation are compendial
`. The drug product composition is attached to this review
`. Manufacturing process involves
`
`m4)
`
`0) (4)
`
`Whether adequate iii-process tests are in place
`to ensure thatproduct quality does not deteriorate during hold time should be
`verified.
`. Table 2 in Section 3.2.P.3.3 provides a summary of the batch lots used in clinical
`and stability for which executed batch records have been provided.
`. The DP specification is attached for quick reference. The company has proposed
`separate release and regulatory specification with differences in acceptance
`criteria for pH, osmolality, benzalkonium chloride and EDTA. The acceptance
`limits for
`M“) is set at NMT (um) and total impurities at NMT mm) The
`impurities listed in Table 1, Section 3.2.P. 5.1 does not list those specified in Table
`4, Report S00156—R (Stability Reportfrom Primary Stability Batches of
`Bromfenac Ophthalmic Solution 0.07%). Specifically, the above referenced
`report, the specification includes test and acceptance limitfor
`at NMT mm The reporting ofthe impurities
`requires careful scrutiny and also consulted with Pharm/Tox on the qualification
`ofthe impurities. The proposed acceptance valuesfor the aforementioned
`(specifically of
`mm) should be evaluated and
`tightened ifneeded based on batch and stability data. Additionally, the proposed
`impurities and the levels should be compared to the currently marketed approved
`product.
`The specification does notprovide a testfor residual solvents. It needs to be
`verified ifpotential residual solvents are controlled in the raw materials. The
`
`(ID) (4)
`
`.
`
`Reference ID: 3164499
`
`

`

`IQA-NDA 203168
`
`.
`
`needfor the company to provide a statement that the drugproduct complies with
`USP <467> can be determined during review.
`. While providing testsfor sodium sulfite and weight loss (the later is proposed
`onlyfor stability), the drugproduct specification does notprovide acceptance
`criteriafor both attributes. The company shouldpropose appropriate acceptance
`limitsfor these quality attributes.
`. As indicated earlier, bracketing approach has been used in supporting stability of
`the variousfill sizes proposed. The proposed trade sizes are 1.6 mL and 3.0 mL
`and the proposed sample sizes are 0.6 ml. and/or 0.8 mL. Stability studies have
`used 0.6 mL, 1.0 mL, 1.5 L, and 3.0 mLfill sizes which brackets the 0.8 ml sample
`size and the 1.6 mL trade size. What, ifany, efirects ofthe (difl'erent) headspace in
`the various packaging configurations have on the quality ofthe product over the
`shelf-life should be assessed.
`The trend in quality attributes on stability should be evaluated in considering the
`proposed shelf-life of22-months and how it aflects, ifany the shelf-life attributes
`ofthe drugproduct. Any correlation between the observed trends may aid in the
`tightening ofthe specification and in determining the appropriate shelf-life. For
`example, is the observed trend in assay values influenced by the weight loss/gain?
`Among the quality attributes tested, the trends are prominent with osmolality,
`assayfor sodium sulfite (note there is a significant drop in value in the initial
`stages) and weight loss irrespective ofthe orientation. The trends are even more
`pronounced under accelerated conditions. In addition to the eflect on quality, the
`other question to consider is, how will the drugproduct, for marketing, be
`shipped and iftransportation storage conditions will impact the quality ofthe
`product.
`The leachable study has identified several organic volatile and organic semi-
`volatile leachables peaks and several unidentified (see above referenced report).
`Two peaks tentatively identified as
`mm and
`out)
`and several other leachables were detected at levels above the identification and
`qualification threshold of> Lug/g. Report $00245-R (Appendix 4) provides a
`safety evaluation ofthese compounds. Whether the origin ofthese leachables has
`been traced is unclear. Though a safety report has been provided, given the
`plethora ofleachables, a toxicology consult should be considered to ensure that
`the levels ofthe various leachables pose no safety risk. Also, it should be
`determined during review ifthe leachable(s) should be included in the DP
`specification with appropriate acceptance limits.
`m” Whether residual levels
`. The container closures are
`"a, are controlled should be checked.
`of mm and
`. The carton and container labels mentions “Sample-Not for sale”. Whether this is
`acceptable or should the label specifically state “Physician sample ” may be
`discussed with Clinical/DMEPA.
`
`.
`
`.
`
`The NBA does notprovide the color mock ofthe container and carton labels. This
`should be communicated in the 74-day letter to the company.
`
`Reference ID: 3164499
`
`

`

`IQA-NDA 203168
`
`Early action needed:
`
`1) Reviewer should evaluate items identified (in italics) in this IQA.
`
`Comments for 74-day letter
`
`The following comments will be communicated to the company.
`
`1. Please submit color mock of the carton and container labels
`2. The drug product specification proposes a test for weight loss and sodium sulfite but
`does not provide for acceptance criterion. Please propose a suitable acceptance limit
`for this test.
`
`Comments and Recommendation:
`
`Based on the perusal of this NDA, it is determined to be complete and therefore filable
`from CMC perspective. Dr. Rao Kambhampati is assigned to review this NDA.
`
`
`Balajee Shanmugam
`CMC Lead
`
`
`
`Rapti Madurawe, Ph.D.
`Branch Chief
`
`
`
`
`
`
`
`
`
`
`
`See DARRTS
`
`
` Date
`
`
`
`
`See DARRTS
`
` Date
`
`Reference ID: 3164499
`
`5
`
`

`

`IND 60295
`Meeting Minutes
`Type B
`
`Division of Transplant and Ophthalmology Products
`
`
`MEMORANDUM OF MEETING MINUTES
`
`
`Meeting Type:
`Meeting Category:
`
`Meeting Date and Time: August 29, 2011, Start: 9:05, End: 9:25
`Meeting Location:
`Bldg 22, Room 1313
`
`Type B