CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208144Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`1 . 12.14 Environmental Analysis
`
`1.12.14 Environmental Analysis
`
`Bausch & Lomb, a division of Valeant Pharmaceuticals North America LLC. hereby claims
`that the action requested of approval of this new drug application (NDA) for brimonidine
`tartrate ophthalmic solution, 0.025%, , qualifies for a categorical exclusion and therefore does
`not require the submission of a full environmental assessment per 21 CFR 25 .3l(b).
`
`This is an additional brimonidine taitrate-containing drug product that will have little to no
`contribution to the aquatic or terrestrial environment, compared to the 1.0 PPB threshold
`outlined in 21 CFR 25.3 1(b). The calculation below is from the FDA Guidancefor Industry:
`Environmental Assessment of Human Drug and Biologics Applications ", July 1998, and is
`used to estimate the potential concentration of the substance at the point of entry into the
`aquatic environment.
`
`Basic assumptions
`0 Compound in use is brimonidine tartrate
`0 Quantity of active per proposed commercial and sample use is
`
`W" per year
`
`The expected introduction concentration (EIC) of brimonidine tartrate into the aquatic
`environment is calculated as follows:
`
`ElC Aquatic (PPB) = A*B*C*D
`A = kg/year of product use
`B = l/liters per day entering publicly owned treatment works (POTW) (1.214
`X 10” liters per day standard)
`C = year/365 days
`D = 109 rig/kg (conversion factor)
`
`Brimonidine tartrate calculation:
`A =
`
`D) (4)
`
`(b) (4)
`
`mm)
`
`Result: A*B *0ch =
`
`mu)
`
`This result is well below the 1.0 PPB threshold outlined in 21 CFR 25.31(b). Therefore, a
`categorical exclusion from further environmental assessment under 21 CFR 25 is requested.
`(h) (4)
`
`(II) (4)
`
`_ 3.03/15"
`
`Reference ID: 4202276
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MELISSA V CHHANGTE
`01/02/2018
`
`Reference ID: 4202276
`
`

`

`
`



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`
`

`

`3. Labeling: Storage Statement: OPQ quality review (dated 11/6/17) recommended
`strengthening the storage statement by adding a warning against storage at high
`temperatures e.g. “discard if the product if stored at any temperature above 30°C
`(86°F)”. The recommendation was based on changes in the pH, osmolality and
`concentration of the drug product seen in stability results and was made to assure
`that the quality of the product remained within specifications similar to the
`reference listed drug (RLD) when used by the consumer in an over-the counter
`setting. However, DTOP (Division of Transplant and Ophthalmology Products)
`clinical review (dated 11/27/17) advised that the warning statement “is not
`warranted fiom a clinical prospective” since “changes in pH and osmolality do not
`reach levels that are likely to affect the safety or efficacy of the drug product”.
`Thus, OPQ defers decision regarding the discard statement to the DNDP labeling
`team.
`
`
`

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`Swapan
`«Ti: De
`‘
`‘
`
`  
`
`
`Digitally signed by Swapan De
`Date: 12/01/201712:11:26PM
`GUID: 508da7220002a1 1432909e07775b6e02
`
` 
`
`ÿ ÿÿ  ÿ
` ÿÿ
`ÿ ! 
`
`

`

`3°
`
`3’ C
`
`.5
`7%
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`27 November 2017
`
`TO:
`
`Thao Vu
`
`Regulatory Health Project Manager
`CDER/OPQ/OPRO
`
`FROM:
`
`Elizabeth Bearr, Ph.D.
`Microbiologist
`CDER/OPQ/OPF/Division of Microbiology Assessment
`(240) 402-4467
`
`THROUGH: Erika Pfeiler, Ph.D.
`Quality Assessment Lead (Acting)
`CDER/OPQ/OPF/Division of Microbiology Assessment
`
`SUBJECT: Addendum to NDA 208144 microbiology review N208144MRO] .doc
`Submission Date: 1 1/17/2017
`Drug Product: brimonidine tartrate ophthalmic solution 0.025%
`App icant: Bausch & Lomb, a wholly-owned subsidiary of Valeant
`P armaceuticals International Inc.
`
`The Division of Nonprescription Drug Products (DNDP) requested that the Division of
`Microbiology Assessment provide an addendum to the microbiology review of NDA 208144 to
`address whether the labeling statement “Discard remaining product 120 days after opening”
`should remain or be removed from the final product label. From the microbiological perspective,
`the risk to the patient due to microbial contamination after product opening is considered low
`based on the following data:
`
`0 USP <51> testing (AET) was performed on the drug product formulated with
`preservative levels ranging from
`m)«)%_ The drug product formulated at
`of the preservative label claim met the USP <51> criteria for adequate preservative
`effectiveness for a Category 1 product. It is expected that the preservative content would
`need to degrade by more than 33% before a contamination event led to excessive
`microbial growth.
`0 An in-usc study was conducted wherein 2 drops of the drug product were dispensed
`every other day for 121 days. The drug product was capable of passing AET after 121
`days of simulated use.
`
`(m4)%
`
`Reference ID: 4202276
`
`

`

`MEMORANDUM
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`o AET was performed on drug product stability samples stored unopened at 25°C for 24
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`months (i.e. expiry for the “worst case” 7.5 mL drug product) and the samples met the
`
`
`acceptance criteria.
`
`
`
`
`
`
`
`
`
`
`
`
`Based on these data, DMA recommends that standard labeling practices concerning discarding
`
`
`
`
`
`
`opened multi-dose ophthalmic products be followed.
`
`
`
`END
`
`
`
`Reference ID: 4202276
`Reference ID: 4202276
`
`
`
`

`

`
` ,.
`% Elizabeth
`
`:69 g5 Bearr
`
`
`m v"
`
`
`
`
`l
`(x1; Erika
`
`V »
`v5 Pfeiler
`
`
`
`
`
`Digitally signed by Elizabeth Bearr
`
`
`
`
`Date: 11/27/2017 12:01:32PM
`GUID: 55370d1eOchd67ch4d8bfbedbf3096
`
`
`
`
`
`
`
`
`
`
`
`Digitally signed by Erika Pfeiler
`
`
`
`
`Date: 11/27/2017 11:58:31AM
`GUID: 502d1da500002b6a73a0000e0dff6e1d
`
`
`
`
`
`
`Reference ID: 4202276
`Reference ID: 4202276
`
`

`

`I I UALITY ASSESSMENT
`
`EXECUTIVE SUMMARY
`
`NDA 208144
`
`Review # 1
`
`Recommendation: APPROVAL
`
`Drug N Mlle/Dosage Form
`
`LuminesseTM (brimonidine tartrate ophthalmic
`solution)
`
`m_ 0.025%
`Route of Administration
`Toical auhthalmic
`Rx/OTC Di ensed
`
`Bausch & Lamb, a wholly-owned subsidiary of Valeant Pharmaceuticals
`International Inc.
`
`US aent ifa licable
`
`SUBMISSION S REVIEWED
`
`DOCUMENT DATE
`
`DISCIPLINE S AFFECTED
`
`O riginal (SD 0000)
`
`31 Mar-2015
`
`NDP/OPF
`
`NDP/OPF
`
`NDP/OPF
`0NDP
`
`0NDP
`
`DISCIPLINE
`
`0 uali Review Team
`REVIEWER
`
`BRANCH/DIVISION
`
`Martin Haber PhD.
`
`ONDP/DNDP-Il/ Branch VI
`
`Swa-an K. De PhD.
`
`ONDP/DNDP—II/ Branch VI
`
`
`EnvironmentalAssessment (EA)——
`
`_———
`Regulatory Business Process
`OPRO/DRBPMl/RBPMBI
`Mana 1 er
`A- olication Technical Lead
`Laborato OTR
`ORA Lead
`
`Paul Perdue
`
`ORA/OMPTO/DMPTPO/MDTP
`
`NBA-208144
`
`Executive Summaryl
`
`

`

`
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMF
`
`YPE
`
`m Type III
`
`Type III
`
`Type III
`
`Type III
`
`Type III
`
`—
`Type III
`
`(”’"21-Jan-
`2013
`
`18-Jun-
`
`2013
`
`12-Dec-
`2014
`
`21-Jan-
`2013
`
`28-Jun-
`
`2013
`
`24-Jul-
`
`2014
`
`REVIEW
`COMPLETED
`Active
`
`‘ ctive
`
`OMMENTS
`
`Sufficient data in the
`application.
`
`The DMF and the
`components have
`been neviewed in by
`Dr. Yushi Feng, PhD.
`(23- Aug—2016), and
`were found to be
`adeuate.
`
`Sufficient data in the
`application.
`
`Sufficient data in the
`application.
`
`The DMF and the
`components have
`been reviewed in by
`Dr. Joel Hathaway,
`PhD. (04- May-
`2016), and were
`found to be ade-uate.
`The DMF and the
`components have
`been reviewed in by
`Dr. Ping Jiang—
`Baucom, PhD. (1 l-
`May-2015), and were
`
`found to be adequate.
`
`lAdequat
`applicatio
`
`st, Deficient, or N/A (There is enough data in the
`be reviewed)
`
`B. Other Documents: IND, RLD, or sister applications
`
`DOCUMENT
`
`ANDA
`
`APPLICATION
`NUMBER
`20-613
`108524
`076260
`
`Brimonidine Tartrate O uthalmic Solution 0.20%
`
`DESCRIPTION
`Alu_haan Brimonidine Tartrate o thalmic Solution 0.2%
`Brimonidine Tartrate o uthalmic Solution 0.025%
`
`NBA-208144
`
`Executive SummaryZ
`
`

`

`
`
`2. CONSULTS:
`
`DISCIPLINE
`
`STATUS
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`CDRH ——_—
`
`—_—_—
`Pharmacology/Toxicology——_—
`
`NBA-208144
`
`Executive Summary3
`
`

`

`
`
`Table of Contents
`
`Table of Contents ............................................................................................ 4
`
`Quality Review Data Sheet .........................................Executive summary 1-3
`
`Executive Summary ........................................
`
`Executive summary 5-11
`
`ASSESSMENT OF THE DRUG SUBSTANCE-------------------------------Drug Substance 1-17
`
`2.3.S
`
`DRUG SUBSTANCE-----------------------------------------Drug Substance1-17
`
`ASSESSMENT OF THE DRUG PRODUCT-------------------------------Drug Product 1-43
`
`2.3.P
`
`DRUG PRODUCT----------------------------------------Drug Product 1-43
`
`ASSESSMENT OF THE PROCESS----------------------------------------Process review 1-14
`
`2.3.P
`
`DRUG PRODUCT ................................................. Process review 1-14
`
`ASSESSMENT OF THE BIOPHARMACUETICS ........................N/A
`
`ASSESSMENT OF THE FACILITIES .........................................................FR Page 1-7
`2.3.S
`DRUG SUBSTANCE ........................................................FR Page 1-2
`
`2.3.P
`
`DRUG PRODUCT ...............................................................FR Page 1-7
`
`ASSESSMENT OF MICROBIOLOGY .........................................................Micro 1-43
`
`Container/Closure System .......................................Drug product review Page 20-25
`
`ASSESSMENT OF ENVIRONMENTAL ANALYSIS ...................... Drug product 31
`
`Labeling & Package Insert ........................................................Drug Product Labeling 32-33
`
`NDA-208144
`
`Executive Summary4
`
`

`

`
`
`Executive Summary (NBA-208144)
`Recommendations
`
`I.
`
`Regarding Chemistry Manufacturing and Controls, the application may be approved.
`A. Recommendation and Conclusion on Approvability
`Regarding quality aspects of the application the drug substance, drug product, process,
`microbiology and facility sections are reviewed and found adequate to support the
`approval of the application. The drug product has been granted a shelf life of
`15 months for the 2.5mL fill and 24 months for the 7.5mL fill product configuration. In
`addition, 120 day in-use period is granted (i.e. once the bottle is opened it should be
`discarded afier 120 days).
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable: N/A
`
`Summary of Quality Assessments;
`11.
`The application is a resubmission following a “refuse to file” letter from the Agency
`dated May 29, 2015 due to lack of post-marketing data critical for an adequate safety
`review of the product for proposed use in an over-the counter (OTC) consumer
`population. The application is resubmitted on February 27, 2017.
`Quality information for the drug substance, drug product, manufacturing process,
`microbiology and facility are included in the quality overall summary section and is
`acceptable. Some basic information is shown below.
`1. Drug Substance [USAN Name] Quality Summary
`Chemical Name or IUPAC Name/Structure: 5-Bromo—N—(4,5-dihydro-1H-imidazol-2-yl)-
`6-quinoxalinamine L-Tartrate.
`USAN: Brimonidine Tartrate
`
`Formula: (C1 lHloBrN5.C4H606).
`CAS Number 70359-46-5
`
`MW: 442.22 g/mol
`
`'1'
`
`Br
`
`m.
`
`. 9H
`
`N;
`
`HOZC/\§/
`6H
`
`co H
`
`2
`
`NBA-208144
`
`Executive SummaryS
`
`

`

` ,
`
`W"
`
`«1114)
`
`has
`DMF
`The approved suppliers of Brimonidine tartrate is
`been reviewed at least 18 times, most recently on 3/ 1/2017 by Dr. Simon Peng and found
`adequate. LoA dated 12/4/2014 is provided in the original NDA (see drug substance
`review).
`Specifications follow current compendial monographs. Specifications include description,
`identification (IRand HPLC RT), solution pH
`(m4), LOD (NMT ”.%1 residueb(04p
`ignition (NMT“, 0%) heavv metals (NMT
`MW), assay (
`mu)%
`,
`related substances (
`”NMT "Mb/o, any other irnnuritvmNMT ”WM: and
`total imRigities NMT“,114%) residual“solvents (
`m4) NMT
`4)1.
`m4)
`% of label claim or
`«1%
`m4) optical rotation
`(b) (4)
`(b) (4)
`and bioburden (total aerobic count NMT
`yeast/mold count NMT
`absence of S. aureus, P. aeruginosa, E. coli, Salmonella spp., B. cepacian.
`
`mu)
`.
`.
`.
`1pm)
`is sttored at
`Brimonidine tartrate
`”wand a gimonth re-test period is assigned based on stability data
`from long term and accelerated storage conditions.
`
`NDA-208144
`
`Executive Summary6
`
`

`

`
`
`A. Drug Product [Established Name] Quality Summary
`1. Strength: 0.025%
`
`2. Description/Commercial Image:
`The proposed OTC drug product is LuminesseTM (0.025% brimonidine tartrate
`ophthalmic solution). It will be marketed as a vasoconstrictor for the relief of eye
`redness due to minor eye irritations in adults and children 5 years of age and older.
`Dosing regimen is 1 drop in affected eye(s) every 6-8 hours, no more than 4 times daily.
`The product will be available in two configurations 2.5 mL and 7.5 mL fill volume and these
`volumes (2 configurations) will also be used for physician samples.
`
`3. Summary of Product Design
`The applicant has used a similar process for their approved marketed drug product (ANDA
`076260), Brimonidine Tartrate Opthalmic Solution, 0.2% and referred the application for
`detailed manufacturing process.
`
`4. List of Excipients:
`Benzalkonium Chloride, Boric Acid, Calcium Chloride Dihydrate, Glycerin, Potassium
`
`
`
`NBA-208144
`
`Executive Summary7
`
`

`

`
`
`6. Container Closure:
`
`The product is packaged in a 10mL round white low-density polyethylene (LDPE) bottle
`fitted with a
`(mo
`dropper tip and closed with a child-
`om)
`(no)
`
`outer and a
`resistant cap composed of a purple
`com) inner closure. Primary packaging components are tested and sterilized with
`(b) (4)
`
`The bottle is fitted with a clear tamper resistant neckband and an adhesive label, then
`packaged in a carton.
`7. Expiration Date & Storage Conditions
`Proposed expiry of 15 months for the 2.5mL fill and 24 months for the 7.5mL fill product
`is acceptable and supported by the real-time stability data from for 3 registration lots for each
`fill, plus one clinical lot and one commercial lot for each fill (See attached: drug product
`review).
`Based on in-use stability data for both 2.5 mL and 7.5 mL configurations, 120 day in-use
`period is granted. “Discard 120 days after opening the bottle” is suggested to be in the label.
`The storage statement will be written as “Store at 15° m“’25°C (59°F W" 77°F)”.
`
`8. List of co-packaged components: None
`
`B. Summary of Drug Product Intended Use
`
`Proprietary Name of the Drug ”0‘1““
`
`N0“ Proprietary Name of the Drug PrOdUCt
`
`I: rimonidine Tartrate Opthalmic Solutio
`0.025%
`
`Alternative Men-ads «Administration _
`
`Non Proprietary Name of the Drug Substance
`
`|: rimonidine Tartrate
`
`Proposed lndication(s) including Intended
`Pane!" Population
`
`I' elieve redness of the eye due to minor eye
`irritations. Adults and children 2 5 years
`
`_ d‘°" m “‘6 “”fe“ eye“) “6” 6'8 h”
`
`. to 4 times/da
`
`MaXimum Daily Dose
`
`s cc “duration of treatment”.
`
`C. Biopharmaceutics Considerations
`1. BCS Classification: Not applicable (BCS class is determined only when
`applicant proposed the product as BCS Class I.
`0 Drug Substance:
`
`NBA-208144
`
`Executive Summary8
`
`

`

`
`
`0 Drug Product:
`
`2. Biowaivers/Biostudies—
`o Biowaiver Requests: No
`0 PK studies: N/A
`
`0 IV I V C: No
`
`D. Novel Approaches
`E. Any Special Product Quality Labeling Recommendations
`Established name of the drug product remains “Brimonidine tartrate ophthalmic solution”
`as approved in the prescription ANDA 076260, although based on current FDA guidance
`(“Naming of drug products containing salt drug substances guidance for Industry”-June
`2015) and USP salt policy of the active moiety, the established name should contain the
`active moiety in neutral form without the name of salt. However, to avoid confusion
`with the prescription product the established name for the OTC product is accepted as
`proposed “Brimonidine tartrate ophthalmic solution”.
`LuminesseTM
`
`(brimonidine tartrate ophthalmic solution 0.025%)
`Based on stability data following labeling recommendation needs to be discussed.
`0 Warning to discard the product if the product was stored at any temperature
`above 30°C (86°F)
`
`0 Discard 120 days after opening the bottle.
`
`F. Life Cycle Knowledge Information (see table below)
`
`Product
`
`Factors that
`
`Probability
`
`Severity
`
`Detectability
`
`FMECA
`
`attribute/CQA
`
`can impact
`the CQA
`
`(0)
`
`of Effect
`(S)
`
`(D)
`
`RPN
`Number
`
`specifications
`(USP)
`
`Meets USP, light
`obscuration.
`
`
`
`Sterility
`
`- Formulation
`- Raw materials
`- Process
`
`2
`
`3
`
`2
`
`8
`
`Meets USP<61>.
`
`NBA-208144
`
`Executive Summary9
`
`- Scale/equipmen Osmolality
`
`Assay, stability
`
`- Formulation
`
`- Raw materials
`- Process
`
`parameters
`
`' Formulation
`
`- Raw materials
`' Process
`parameters
`- Scale/equipmen
`
`' Formulation
`Container
`closure
`- Raw materials
`- Process
`
`parameters
`
`2
`
`2
`
`3
`
`2
`
`2
`
`2
`
`2
`
`2
`
`2
`
`l2
`
`Controlled through
`
`specifications.
`
`Controlled through
`
`

`

` ° Scale/equipment
`
`° Site
`
`NBA-208144
`
`Executive Summarle
`
`

`

`
`
`OVERALL ASSESSMENT AND SIGNATURES: EXECUTIVE
`
`SUMMARY
`
`
`
`NBA-208144
`
`Executive Summaryll
`
`

`

`  
`
`
` 
`
`ÿ ÿÿ  ÿ
` ÿÿ
`ÿ ! 
`
`60 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`MIg 2R! 2B1! 2L! 25 iY
`
`Product Background: -
`
`NDA: 208144
`
`Drug Product Name / Strength: Luminesse (Brimonidine Tartrate Ophthalmic Solution) /
`0.025%
`
`Route of Administration: Topical ophthalmic
`
`Applicant Name: Bausch & Lomb, a wholly-owned subsidiary of Valeant Pharmaceuticals
`International Inc.
`
`Manufacturing Site: Bausch & Lomb, Inc., 8500 Hidden River Parkway, Tampa, FL 33637
`(um)
`
`Method of Sterilization:
`
`Review Recommendation: The submission is recommended for approval on the basis of
`sterility assurance.
`
`Review Summary: The drug product is
`
`(b)(4)
`
`(b) (4)
`
`List Submissions being reviewed: 3/31/2015, 02/27/2017, 04/28/2017, and 08/02/2017
`
`Highlight Key Outstanding Issues from Last Cycle: N/A
`
`Concise Description Outstanding Issues Remaining: None
`
`Supporting/Related Documents: N/A
`
`Remarks Section: The application was originally submitted on 03/31/2015. The agency
`refused to file the application (RTF letter archived on 05/29/2015). The applicant
`requested a Type A meeting, which was held on 07/29/2015, and a list of DMA comments
`that captured deficiencies in the 03/31/2015 submission were issued with the Preliminary
`Meeting Comments on 07/28/2015. The application was resubmitted on 02/27/2017. DMA
`comments were conveyed in the filing communication on 4/13/2017. The applicant’s
`submission dated 04/28/2017 is in response to deficiencies issued in the filing
`communication dated 04/13/2017. The applicant’s submission dated 08/02/2017 is in
`response to the Agency’s Information Request dated 07/26/2017.
`
`

`

`QUALITY ASSESSMENT
`
`S Drug Substance — N/A, non-sterile
`
`P.1 Description of the Composition of the Drug Product
`0 Description of drug product — The drug productis a sterile, aqueous—based solution for
`topical ophthalmic administration, pH
`(mcontaining 0.025% brimonidine tartrate,
`7.5 mL and 2.5 mL fill in 10 mL multi-dose bottles.
`
`0 Dru ; roduct comosition —
`__
`Brimonidine Tartrate
`0
`(m4)
`G1 cerin
`Sodium Borale Decah drate
`Boric Acid
`Potassium Chloride
`Calcium Chloride Dih drate
`Sodium Chloride
`
`(b) (4)
`
`Benzalkonium Chloride §§AK L
`((2)1 Sodium Hydroxide“-
`Hdrochloric Acid
`Water for Ineclion
`a
`
`M ‘4)—
`
`b C
`
`(b) (4)
`
`Descrition of container closure 5 stem —
`
`
`m——
`@114)
`
`
`
`0.025%, 7.5 mL or
`2.5 mL fill
`
`Reviewer’s Assessment: Adequate
`
`The applicant provided an adequate description of the drug product composition and the
`container closure system designed to maintain product sterility.
`
`P.2.5 Microbiological Attributes
`Container/Closure and Package Integrity
`(eCTD seq #0000: Section 3.2.P.2.5 Microbiological Attributes, pp. 3-5)
`
`The container/closure system used for validation was the same as the drug product.
`Container closure integrity was tested by the microbial immersion method. Integrity test
`units were selected from passing (negative for growth) media fill simulation samples.
`Representative process simulation media fill test units were selected from across the
`entire fill. Positive controls were prepared by adding a sanitized insulated wire with a
`minimum 24 gauge to each of 5 units such that the wire would interfere with the bottle/tip
`seal and the tip/closure seal and the units were reassembled. Five growth promotion
`controls were prepared and each consisted of a unit inoculated with < 100 CFU/0.1 mL of
`
`

`

`QUALITY ASSESSMENT
`
`the B. dim inuta challenge organism. The growth promotion units were not exposed to the
`pressure and vacuum. Five negative control units were not immersed in the challenge
`organism, but were exposed to pressure and vacuum. Test units and positive controls
`were submerged in a B. diminuta suspension (106 CFU/mL) for 20 minutes at room
`temperature. Following immersion, the units were placed in a pressure system and 5 psi
`of pressure was applied for 5 minutes followed by a vacuum of ~5” of mercury for 5
`minutes. The challenge units and all controls were incubated at 32.5" :1: 25°C for NLT 7
`days. Containers were then examined for signs of microbial growth (turbidity).
`
`Acceptance Criteria:
`
`0 No B. diminuta isolated from any challenged media container.
`0 All 5 breached controls are positive for growth.
`0 All 5 growth promotion controls are positive for growth.
`
`0 All negative controls are negative for growth.
`
`Results: The results of the study provided below meet all acceptance criteria.
`
`m_ # Posldve/ # Tested
`
`Reviewer’s Assessment: Adequate
`
`The applicant provided adequately validated the integrity of the proposed container-
`closure system.
`
`Antimicrobial Effectiveness Testing
`(Section 3.2.5.1, pp. 1-2)
`
`The procedure used for antimicrobial effectiveness testing was performed according to
`USP <51> The drug product specificationrequires
`“(0% of
`“labelclaim for release and
`(4% of label claim for stability. The AET
`evaluated
`mlevels ranging from 0 — 100%. Lot #: BCL462-016A, BCL462-016G,
`BCL462-016F, BCL462--(b016E, BCL462-016D, BCL462-016C contained 0%, 10%, 25%,
`50%, 75%, and 100%
`respectively.
`
`(b) (4)
`
`Results. The actual plate counts were not provided; however, the applicant states that the
`test articles were inoculated withba minim6)1(r‘1)1 of 1.0 x 105 CFU/mL. The AET results for
`lot #BCL462-016G containing (41% of
`label claim are provided below.
`
`

`

`QUALITY ASSESSMENT
`
`Or- anlsm mum
`
`All lots met the USP <51> criteria for abdgfluate preservative effectiveness for a Category
`1 product except for the lot with no
`
`Reviewer’s Assessment: Adequate
`
`The AET results support the effectiveness of the minimum release and stability
`specifications.
`
`P.3 Manufacture
`
`P.3.1 Manufacturers
`
`Bausch & Lomb, Inc., 500 Hidden River Parkway, Tampa, FL 33637
`Responsible for: drug product manufacturing, packaging, labeling, in-process testing,
`analytical and microbiological release testing for product and excipients, and stability
`testing occurs at this location.
`
`Drug product
`Release/stability testing (as applicable)
`Bausch & Lomb, Inc., 1400 N. Goodman Street, Rochester, NY 14609
`Alternate facility for analytical and microbiological release and stability testing.
`
`P. 3.3 Description of the Manufacturing Process and Process Controls
`Overall Manufacturing Operation
`(eCTD seq #0000: Section 2.3.P, pp. 29-33; Section 3.2.P.2., Manufacturing Process
`Development, p. 12)
`
`The overall manufacturing operation information reviewed below includes the
`information provided in the initial submission dated 3/31/2015. The review also covers
`the information provided in the applicant’s resubmission dated 02/27/2017 in response to
`
`(b) (4)
`
`61 Page(s) have been Withheld in Full as B4 (CCIITS) immediately following this page
`
`