CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208411Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`ll»-£lkl'ill.x- «x. »
`an:
`QUALITY ASSESSMENT
`
`Recommendation: Approval
`NDA: 20841 1
`
`NBA 2084]]
`
`Review #1
`
`
`mu Name/nosaeForm
`
`sm n
`
`Routeomamismon
`
`mm: ms. and
`
`
`Au ulicant
`
`US a_ent ifa: -licable
`
`
`
`
`
`
`SUBMISSION S REVIEWED
`
`DOCUMENT DATE
`
`DISCIPLINE S AFFECTED
`
`
`
`
`O uali Review Team
`REVIEWER
`Venkat Pavulun‘
`Venkat Pavuluri
`Christina Capacci-Daniel
`Edwin Rao
`
`
`
`BRANCHIDIVISION
`0P 0 /ONDP/DNDPAPI/BII
`OP 0 IONDP/DNDPII/BIV
`OPQ/OPF/DIA/IABZ
`
`Microbiology
`
`Facility
`
`Christina Capacci-Daniel
`Erika Pfeiler
`
`Christina Capacci-Daniel
`Grace McNal]
`
`OPQ/OPF/DIA/IAB2
`
`OPQ/OPF/DIA/IAB2
`
`
`DISCIPLINE
`
`
`Dru ; Substance
`
`
`Dru -_ Product
`
`
`Process
`
`
`
`
`
`
`
`
`
`
`
`
`———
`
`
`CDRH OC Combination Products
`Juandria Williams —
`
`
`Environmental Assessment EA—_
`
`Bioharmaceutics
`
`Regulatory Business Process
`Manaer
`' A . . lication Technical Lead
`
`Steve Kinsley
`
`OPQ/OPRO/RBPMI/BI
`
`Julia Pinto
`
`OP O/ONDP/DNDPII/BIV
`
`Reference ID: 3854243
`
`OPQ-XOPQ-TEM-0001V02 Effective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSMENT
`
`Table of Contents
`
`Table of Contents ..................
`
`....................................... . 2
`
`Quality Review Data Sheet .......................................................................... 3
`
`Executive Summary ...........
`
`........................................
`
`................ 4
`
`Primary Quality Review ................................. Error! Bookmark not defined.
`
`ASSESSMENT OF THE DRUG SUBSTANCE .............. Error! Bookmark not defined.
`
`2.3.S
`
`DRUG SUBSTANCE ............................. Error! Bookmark not defined.
`
`ASSESSMENT OF THE DRUG PRODUCT .................................................................. 11
`
`2.3.P
`
`DRUG PRODUCT .....................................................................................
`
`R.2
`
`Comparability Protocols .............................................................................
`
`ASSESSMENT OF THE PROCESS ....................................................................................
`
`2.3.P
`
`DRUG PRODUCT .....................................................................................
`
`R.2
`
`Comparability Protocols .............................................................................
`
`ASSESSMENT OF THE FACILITIES ................................................................................
`
`2.3.8
`
`2.3.P
`
`DRUG SUBSTANCE ................................................................................
`
`DRUG PRODUCT .....................................................................................
`
`ASSESSMENT OF THE BIOPHARMACUETICS ............................................................
`
`ASSESSMENT OF MICROBIOLOGY ...............................................................................
`
`2.3.P.7
`
`Container/Closure System .......................................................................
`
`A
`
`APPENDICES ..........................................................................................................
`
`A.2
`
`Adventitious Agents Safety Evaluation .....................................................
`
`ASSESSMENT OF ENVIRONMENTAL ANALYSIS ......................................................
`
`1.
`
`Review of Common Technical Document-Quality (Ctd-Q) Module 1 ....................
`
`Labeling & Package Insert ................................................................................................ 50
`
`ll.
`
`III.
`
`List of Deficiencies To Be Communicated ...............................................................
`
`Attachments ..............................................................................................................
`
`2
`
`OPQ-XOPQ-TEM-OOOlvOZ Effective Date: 13 Mar 2015
`
`Reference ID: 3854243
`
`

`

`QUALITY ASSESSMENT
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`ITEM
`HOLDER
`— O) REFERENCE”
`09(4) Type II
`Naloxone
`
`STATUS
`
`COMMENTS
`
`DATE
`REVIEW
`COMPLETED
`Oct 2015 _
`
`Type In (If
`aeglicablez
`Type IV (if
`a a I Iicable
`
`Nasal spray
`
`Adequate
`
`October 2105
`
`
`
`
`
`
`
`
`
`
`
`mavmwm
`
`
`
`———_—
`
`———_—
`-—--_2015
`—_———
`—_—-—
`
`
`
`Rick Cha-man
`
`
`
`
`
`3
`
`OPQ-XOPQ-TEM-OOOIVOZ Effective Date: 13 Mar 2015
`
`Reference ID: 3854243
`
`

`

`QUALITY ASSESSMENT
`
`1.
`
`Recommendations
`
`Executive Summary
`
`A. Recommendation and Conclusion on Approvability
`
`Narcan®(Naloxone Hydrochloride) Nasal Spray is intended for use in the
`emergency treatment of opioid overdose and therefore was granted fast track
`designation. The naloxone API is supplied by
`"M"- The drug product is
`formulated
`"M" comprising the following excipients: Sodium
`chloride, disodium edetate, and benzalkonium chloride,
`in a concentration of
`40mg/ml. The container closure System is a glass vial with a
`“9‘" stopper
`which is then encased within a nasal actuator and container holder. The nasal
`
`"’""and has been reviewed by CDRH
`(”munder DMF
`spray device is by
`and OPQ,
`for use with the naloxone drug product. Each unit dose device,
`formulated to deliver one dose of naloxone,
`is placed within a blister package.
`Two units or blister packages are then stored per carton. Adequate data to assess
`the device delivery of the drug product and to assure the identity, strength, purity,
`and quality of the drug product is provided. The drug product is granted an expiry
`of 24 months, when stored at room temperature. Further, the Office of Process
`and Facilities, has made an overall recommendation of adequate for all facilities
`related to this application. Therefore, from a quality perspective, this NDA is
`recommended for approval.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`1. Conduct a Stability study for the Drug Product stored at 4°C and 40°C for 24
`months, to support the storage and excursion statement on the carton and insert
`labels.
`
`Two additional PMCs are have been agreed upon, by CDRH review team and the
`Sponsor. See CDRH Review by Ryan McGowen.
`
`OVERALL ASSESSMENT AND SIGNATURES: EXECUTIVE
`
`SUMMARY
`
`“K‘s".lb‘clz“
`
`Julia C. Pinto -S $255.21“
`
`vam-In—nmms
`
`49 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`4
`
`OPQ-XOPQ-TEM—0001v02 Effective Date: 13 Mar 2015
`
`Reference ID: 3854243
`
`

`

`
`
`filth “' QUALITY ASSESSMENT NDA 208411 ' PM!!!)
`
`
`-" Drug Substance and Drug Product '
`
`
`
`Page I50
`
`1. Review of Common Technical Document-Quality (Ctd-Q) Module 1
`
`Labeling & Package Insert
`
`1. Package Insert
`
`(:1) “Highlights” Section (ZlCFR 201.5700)
`
`Start ofSponsor material
`main—mmm?
`MPH-um!”
`
`”aw—mm
`mwa-mdumys-m
`mull—Iany".
`n ”HI
`I
`k
`W“-
`__u-mm—
`mm “flit-w
`"dflkwfluwnm
`0’ him__..
`
`4.
`
`Mining “twat-RIM”
`
`“HUM
`
`k. W'mum‘uwm
`unsymmmum
`
` %
`
`End ofSponsor material
`
`Infofliiflon Emu! NDA
`
`substance symbol (if
`
`‘
`1 name 201.57 a
`Product titl Dr .
`Proprietary name and Proprietary; NARCAN Nasal
`established name
`Spray
`Established Name: Naloxone
`H drochloride nasal :
`
`Acceptable from
`CMC perspective
`
`Dosage form, route
`of administration
`
`Controlled drug
`
`Reference ID: 3854243
`
`

`

`dVvU'fi‘JIH éi’m'
`
`Drug Substance and Drug Product
`Information Provided in NBA
`
`
`fine-Di
`
`Page |51
`
`mmmm‘
`
`Reviewer’s
`Assessment
`
`
`fing QUALITY ASSESSMENT-NBA 208411
`
`
`
`
`Acceptable from
`A concise summary NARCAN" nasal spray contains a
`
`
`
`CMC pcrspcctlve
`of dosage forms and
`single dose of4 mg of Naloxone
`
`
`strengths
`hydrochloride in 0.1 mL for
`
`intranasal use on]
`.
`
`
`Dosae Forms and Strenths 201.57 a 8
`
`Conclusion: Acceptable from CMC perspective.
`
`(b) “Full Prescribing Information” Section
`
`# 3: Dosage Forms and Strengths 121CFR 20l.57(c[§4[[
`
`_ Information Provided in NBA
`Available dosae forms
`
`0.1 mL intranasal spray.
`
`' nasal spray is
`A description of the identifying NARC
`characteristics of the dosage
`supplied as single dose 0f4 mg
`forms, including shape, color,
`of naloxone hydrochloride in a
`coating, scoring, and
`imirintin_, when a. licable.
`
`Conclusion: Acceptable from CMC perspective.
`
`#11: Description ngCFR 201.57gc1112n
`
`Start ofSponsor material:
`NARC‘AN (naloxone hydrochloride) nasal spray is a pro-filled. single dose intranasal spray.
`9"" Chemically. naloxone hydrochlon'de is the
`hydrochloride salt of 17-Allyl~4,5(1-epoxy-3.l4—dihydroxymorphinan—6-one hydrochloride with
`the following stnicture:
`
`H5
`
`.
`
`.
`
`N- i
`(ll
`~
`\
`1
`
`.
`3
`"-‘LH,
`
`- ml
`
`\
`
`. “
`3
`«5
`u
`
`I]
`’1""‘\HL)
`,
`g”
`.
`>-
`ML)
`
`~‘0 "
`
`CanNOc‘ EC]
`M.W. 363.84
`
`Naloxone hydrochloride occurs as a white to slightly off-white powder, and is soluble in water.
`in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and
`in chloroform.
`
`Each NARCAN contains a single 4 mg dose of naloxone hydrochloride in a 0.1mL intranasal
`spray.
`om)
`
`Inactive ingredients include benzalkonium chloride (perservative), disodimn
`
`Reference ID: 3854243
`
`

`

`afign QUALITY ASSESSMENT - NDA 208411
`
`
`Drug Substance and Drug Product
`
`hum-him.» um
`
`
`p a
`
`t-
`
`.52
`
`ethylenediametetraacetate (stabilizer), sodium chloride, hydrochloric acid to adjust pH, and
`pmified water. The pH range is 3.5 to 5.5.
`
`
`
`
`
`End ofSponsor material
`
`_ Information Provided in NBA
`
`name
`
`administration
`
`nasal r ra
`
`Naloxone Hydrochloride
`Active moiety expression of
`strength with equivalence statement Dihydrate equivalent to 4 mg of
`for salt
`if a- nlicable
`Naloxone H drochloride
`
`
`
`“WW“ CMC
`Perspective
`
`
`
`
`
`
`
`Benzalkonium chloride
`Inactive ingredient information
`(preservative), disodium
`(quantitative, if injectables
`
`
`21 CFRZOI -1 00(b)(5)(iii)), “$th by Ethylenediametetraacetate
`
`
`
`USP/NF names.
`(stabilizer), sodium chloride,
`
`
`hydrochloric acid to adjust pH,
`
`and purified water.
`
`
`
`
`Pharmacolo _ical/ thera eutic class
`Chemical name, structural formula,
`
`molecular weight
`
`
`
`Statement of being sterile (if
`a t I licable
`
`Not applicable
`
`
`
`17-Allyl-4,5a—epoxy-3,l 4_
`dihydroxymorphinan-é-one
`hydrochloride, CI9H21N04° HCl
`M.W. 363.84
`
`If radioactive, statement of
`im - ortant nuclear characteristics.
`
`Not applicable
`
`Other important chemical or
`Soluble in water,
`physical properties (such as pKa,
`
`in dilute acids, and in strong
`solubility, or pH)
`alkali; slightly soluble in alcohol;
`
`
`practically insoluble in ether and
`in chloroform.
`
`
`
`Conclusion: Acceptable from CMC perspective
`
`Reference ID: 3854243
`
`

`

`Cfigfl) QUALITY ASSESSMENT - NDA 208411
`_
`Drug Substance and Drug Product
`
`(xx-um hut-.1; nun
`
`f
`
`,. a 1... e '53
`
`_ Information Provided in NDA
`Stren ; h of dosa _e form
`Available units (e.g., bottles of 1. Carton containing two blister
`100 tablets)
`packages each with a single
`NARCAN nasal sorav.
`
`Adequate from CMC
`Perspective
`
`
`
`Identification of dosage forms, A single 4 mg dose of naloxone
`e.g., shape, color, coating.
`hydrochloride solution filled into a
`scoring, imprinting, NDC
`glass vial fitted with rubber stopper,
`number
`and place in a container holder and
`fitted with intranasal spray device for
`delivering 0.1 mL upon actuation.
`NDC 69574-353-02
`
`Special handling (e.g., protect
`from li_ t, do not freeze
`Storage conditions
`
`Store at controlled room temperature The short term Freeze - thaw
`15°C to 25°C (59°F to 77°F)
`study data provided don't
`excursions permitted between 4°C
`support the stated excursions
`and 40°C (between 39°F and 104°F). between 4°C and 40°C
`(between 39°F and 104°F)
`through the shelf-life of the
`dru -roduct.
`
`Manufacturer/distributor name listed at the end 01' Pl, following Section #17
`
`_ Information Provided in NBA
`Manufacturer/distributor name (21 Distributed by Adapt Pharma, Inc., Adequate from CMC
`CFR 201.1)
`Radnor, PA 19087 USA.
`Per -ective
`
`
`
`Conclusion:l6 Acceptable from CMC perspective, except for the excursions between
`4°C and 40°C (between 39°F and 104°F).
`
`
`2. Labels
`
`Immediate Container Label (Double pack)
`1)
`Start ofSponsor Material
`FRONT
`
`BACK
`
`
`
`fl «mutmSHIV i
`EPl
`:3l
`
`Reference ID: 3854243
`
`

`

`I'Mfi QUALITY ASSESSMENT NDA 208411
`{h‘lukzhu DEM
`Drug Substance and Drug Product
`
`
`
`
`(“CWIIIIUMMV‘.tu-
`
`1’ a 3;. c I54
`
`R__—eviewer’3 Assessment.
`
`Comments on the Information Provided in NBA
`
`arcan® Nasal Spray
`
`Acceptable
`
`nd prominence (21 CFR
`v 01.10(g)(2))
`
`trength (21CFR
`;
`201.10(d)(1); 21.CFR
`01.100(b)(4))
`
`4 mg
`
`
`
`et contents (21 CFR
`01.51(a))
`1 8i rigmber per 21 CFR
`‘
`I xpiration date per 21 CFR
`I 01.17
`
`‘Rx only” statement per 21
`1‘ FR 201.100(b)(1)
`‘
`
`4 mg
`
`LOT_00000
`EXP M M M/YYY Y
`
`ot present
`
`May be considered
`for inclusion based 0
`the available space.
`
`
`
`Storage
`(not required)
`
`I ot present, too little space to fit the text for storage
`onditions.
`
`Given 0n the Blister
`and outer carton
`
`|
`
`.C number
`per 21 CFR 201.2)
`requested, but not required
`1 or all labels or labeling),
`lso see 21 CFR
`
`y 07.35(b)(3)
`Bar Code per 21 CFR
`201.25(c)(2)**
`
`DC 69574-353-02
`
`cceptable
`
`,
`L
`
`l
`
`7
`l
`
`1
`
`‘
`
`77
`
`!
`‘
`
`| ame of
`.1 anufacturer/distributor
`
`Distritntsd by Adan Pharma. Inc.
`Mn“ PA 19087 USA
`
`
`*2] CFR 201.51(h) A drug shall be exempt from compliance with the net quantity declaration required by this section ifit is an 7
`
`ointment Iabeled‘ ‘sample’, “physician s sample", or a substantially similar statement and the contents of the package do not
`exceed 8 grams.
`"Not required for Physician’s samples. The bar code requirement does not apply to prescription drugs sold by a manufacturer,
`repacker, relabeler, or private label distributor directly to patients, but versions of the same drug product that are sold to or used
`in hospitals are subject to the bar code requirements.
`
`Conclusion: Label text acceptable from CMC perspective, except for the missing
`“Rx only” statement that may be considered for inclusion based on availability of the
`space on container label.
`
`Reference ID: 3854243
`
`

`

`p a g e I55
`
`PM!”"QUALITY ASSESSMENT- NDA 20841fi; I'Mf'n
`Drug Substance and Drug Product
`,
`
`i;
`
`Reference ID: 3854243
`
`

`

`(‘ng QUALITY ASSESSMENT - NDA 208411
`Drug Substance and Drug Product
`
`
`I’ a 3 L.
`
`I 56
`
` :o‘mo hogan.“-
`
`“ Comments on the Information rovided in NBA
`Proprietary name, established
`Acceptable font Size
`| ame (font size and prominence
`(FD&C Act 502(c)(1)(A)(i), FD&C
`‘ ct 502(c)(l)(B), 21 CFR
`701.10(g)(2))
`
`.
`
`I
`
`
`
`__1.CFR 201.100(b)(4))
`1 spray per unit
`_ _ _ _ _ _ _ ..
`I
`LOT=0_0000 &_E)_(_P MMNL/[YYY
`
`
`
`l—otnumber per 21 CFR 201 18
`
`I xpiration date per 21 CFR
`901.17
`
`01 provided.
`
`I ame of all inactive ingredients
`(except for oral drugs);
`3. antitative ingredient
`information is required for
`i'nj ectables)[ 201.10(a),
`v 1CFR201 .100(b)(5)(iii)]
`
`Sterility Information (if
`. pplicable)
`
`ot Applicable
`
`‘Rx only” statement per 21 CFR Included
`7 01.100(b)(1)
`Storage Conditions
`
`Store at rooni temperature liggween
`Protect from Ii . ht
`
`I DC number
`
`per 21 CFR 201.2)
`requested, but not required for
`». ll labels or labeling), also see 21
`FR 207.35(b)(3)
`
`l : at Code per 21 CFR
`01.25(c)(2)**
`ame of
`. anufacturer/distributor
`
`MUG 69547-353412
`
`Distributed by Adapt Pharma, Inc. Radnor, PA 19087 USA
`
`‘See package insert for dosage
`information” (21 CFR 201.55)
`
`“See Enclosed Quick Start Guide”
`
`‘Keep out of reach of children" Optional information Not present
`optional for Rx, required for
`0 TC)
`
`I’ oute of Administration (not
`.equired for oral, 21 CFR
`01.100(b)(3))
`
`or use in the nose only
`
`Reference ID: 3854243
`
`

`

`
`
`Reference ID: 3854243
`
`

`

`QUALITY ASSESSMENT - N DA 208411
`Drug Substance and Drug Product
`
`Strength (21CFR 201.10(d)(1);
`1 .CFR 201 .100(b)(4))
`
`1
`I xpiration date per 21 Cl R
`V 01 . 1 7
`
`I ame of all inactive ingrédients
`‘ except for oral drugs);
`0 antitative ingredient
`'nformation is required for
`fnjectables)[ 201.10(a),
`r 1CFR201.100(b)(5)(iii)]
`
`in 0.1 mL of nasal spray.
`
`Exp DATE : MMM ‘an'
`
`Inactive ingredients information included
`
`Sterility Information (if
`pplicable)
`
`ot Applicable
`
`‘Rx only” statement per 2| CFR Included
`01.100(b)(l)
`-
`'
`Storage Conditions
`
`sronut noon
`mmmmhwndixo
`DONOTFEEE
`
`I DC number
`per 21 CFR 201.2)
`requested, but not required for
`a ll labels or labeling), also see 21
`: FR 207.35(b)(3)
`
`:ar Code per 21 CFR
`0 l .25(c)(2) **
`
`nu anufacturer/distributor
`
`NDC SEEM-35302
`
`A‘DAPT
`PHARMA
`“$1de hymn Pull". Inc.
`mm, PA 1997 USA AIM!"
`
`“— Comments on the nformation Provided in NBA
`:' roprietary name, established
`Acceptable font Slze
`1. ame (font size and prominence
`(FD&C Act 502(c)(1)(A)(i), FD&C
`- ct 502(c)(l)(B), 21 CFR
`01-10(g)(2))
`
`
`
`.‘See Paékage insert for dosage
`Information” (2] CFR 201.55)
`
`OPEN HERE m ouucx sum Gum?
`
`In addition to the statement, a shorter version (quick
`start guide) was included on the carton.
`
`‘Keep out of reach of children” Optional information Not present
`optional for Rx, required for
`a TC)
`
`' oute of Administration (not
`. equired for oral, 21 CFR
`v 01.100(b)(3))
`
`or use in the nose only
`
`Reference ID: 3854243
`
`

`

` {HMED QUALITY ASSESSMENT — NDA 208411
`
`Drug Substance and Drug Product
`
`l’ug. t' [59
`
`
`Mathew: slum .
`
`
`Conclusion: Carton text acceptable from CMC perspective.
`
`[1.
`
`List of Deficiencies Communicated
`
`A. Drug Substance
`
`1. Provide a Certificate of Analysis for the drug substance batches used in the
`preparation of the drug product clinical batches.
`
`B. Drug Product
`
`1. Provide a specification for total impurities in the drug product release and stability
`specifications.
`
`The chromatograms provided in the validation reports for the HPLC methods are
`unclear. Provided clear chromatograms to support the validation reports for the
`HPLC analytical methods
`
`‘5’”) both
`Provide information on the solvent used, (purified water
`during product development and in the manufacturing of the individual clinical lotsone
`
`Both Lot number and Batch numbers were used in the executed batch records. In
`
`section 3.2.P.8.1 stability summary, in table R8. 1 -l and other places the lot numbers
`of executed batches were referred to as batch numbers. Provide information on in—
`
`house procedures in place for assigning lot number and batch number for drug
`product(s) and use correct designations in the submission in all places referring to a
`Lot or Batch number.
`
`In section 2.2 Introduction, table 2.2-l, the standards /grade for all the components of
`drug product were stated as USP and these do not match with what was stated in
`table P. 1 .2-1 in section 2.3.P. 1. Provide the correct material description,
`specifications and quantitative composition statements /information for the drug
`product.
`
`In various sections of the submission the amount of Benzalkonium Chloride present
`in the composition is stated differently, i.e
`one without
`stating whether it refers to the commonly available
`“9‘"
`Benzalkonium Chloride. Provide the correct description and corresponding percent
`w/v or milligrams for Benzalkoniungbghloride throughout the submission, either as
`“Benzalkonium Chloride
`or “Benzalkonium Chloride
`(“"9
`
`per EP/NF description.
`
`Correct the typo in development report, section 2.3.P: “Experiments 12-17 were
`designed to study the effect of adding
`PM”. It
`should be
`(”mu
`
`In section 3.2.P.2.5 Container Closure System of pharmaceutical development, it was
`mentioned that LC-MS, GC-MS, inductively coupled plasma/optical emission
`spectroscopy (ICP-OES) and ion Chromatography were used for analysis of organic
`and inorganic extractables from
`W" Stoppers. Provide the
`location in your NDA submission where the final study rcport(s) for these extraction
`
`Reference ID: 3854243
`
`

`

`
`
`extraction report(s) that include details of the analytical methods used, test results of
`individual extraction studies, and verification / validation of the analytical methods
`employed in identification of extractables using various solvent indicated, i.e. water,
`— ete-
`
`9.
`
`In section 2.3.8.1 Drug Substance: General Information two differen
`
`10. Provided Certificates of Analyses (CoAs) for all the incoming materials used in
`manufacturing of all the Drug Product batches included in the submission, i.e. Drug
`Substance, Excipients, individual components of the Container Closure System
`components_
`- etc. to section 3.2.R.
`
`11. Provide enlarged and readable chromatograms of standard solutions and drug
`product samples, preferably samples from forced degradation studies for the assay
`of naloxone HCL nasal spray, and those generated during validation of the
`following analytical methods.
`
`
`
`12. Update the relevant sections of the submission to include the newly provided quality
`information, i.e. Certificates of Analysis for incoming materials (Drug Substance,
`Excipients etc.) used in the manufacturing of the drug product lots, materials in
`response to information request.
`
`C. Labeling Information
`
`1. Provide revised label text for the container (UnitDose device) with “Rx only”
`included.
`
`2. Provide revised text on the carton and blister to contain “Store at room temperature
`between— “Do Not Freeze” “Protect from light”. Also
`update section 16 of the Prescribing Information to reflect these changes to storage
`conditions.
`
`Reference ID: 3854243
`
`

`

` amt!) QUALITY ASSESSMENT - NDA 208411
`
`
`
`Drug Substance and Drug Product
`
`‘
`
`Ill. Attachments (Life Cycle management)
`
`a Dru Product
`
`Attribute/
`
`Factors that
`
`can impact the
`
`Initial Risk
`
`Ranking*
`
`Risk
`
`Mitigation
`
`Lifecycle
`Considerafions/
`Comments“
`
`Final Risk
`Evaluation
`
`Acceptable or
`Not
`
`Acce . table
`
`
`
`Stability (DP)
`
`Formulation
`Raw materials
`
`Process parameters
`(5)“)
`
`Analytical
`Methods
`
`Validation
`Reference standards
`for each known
`
`impurity
`
`Narcan did not
`
`exhibit increase
`in
`one
`
`0"“) content
`
`during release
`and on (photo)
`stability testing
`of DP.
`
`The levels of
`
`specified
`impurities were
`below the
`
`threshold for
`
`identification
`
`through the end
`of shelf-life
`
`*Risk ranking applies to product attribute/CQA
`"For example, critical controls, underlying control strategies assumptions, post marketing commitment,
`knowledge management post approval, etc.
`
`storage.
`
`Reference ID: 3854243
`
`

`

`QUALITY REVIEW
`
`IV. Administrative
`
`A. Reviewer’s Signature
`
`Dignaly signed byVenkateswara R Pawn-1 <A (Affiliate)
`ven kateswa ra R. PaVU I U ri 'A DN:c=-U$, o=U.S.Govemmem, ou=HHS. ou=NIH, ou=People.
`03.23411 9200300.! 00.1.1 =001 1799946. mzvmleswaia R. Pavuiuri -A
`:JAaftfl3315JL1815240208 0500'
`
`(Am I late)
`
`B. Endorsement Block
`
`Reviewer Name/Date: [Venkateswara R. Pavuluri, Nov 1, 2015]
`Secondary Reviewer Name/Date: [Julia C. Pinto, Nov 1, 2015]
`Project Manager Name/Date:
`
`O
`
`l
`u I
`
`I
`I n
`
`.
`
`_
`
`Digitally signed by Julia C. Pinto —S
`DN:¢=US, o=U.S. Government,ou=HHS, ourFDA,ou=People.
`cnajulia C. Pinto -S, 0.9.2342.19200300.100.1.1=1 300366849
`Date;2015.11.18 14:17:07 05'00'
`
`Reference ID: 3854243
`
`

`

`Updated Labeling & Package Insert: November 17, 2015
`
`The Sponsor requested a change in the excursion temperature statement that is pan of the storage
`statement on carton and PI labels. The requested storage conditions—
`—” was changed to “ store at 15m (so-77°F),
`excursions permitted to 4°C to 40°C (39-104°F)”. The reason for the change, is that the product is
`intended to be stored in all police cars and ambulances in the USA. Therefore the product could
`be stored for long periods of time at temperatures below zero to over 100 °F.' Some limited data
`is provided in the NDA that includes stability data for 40 °C storage for 6 months, and freeze —
`thaw cycling data. It was therefore requested for the Sponsor to agree to a PMC, that includes
`conducting a full stability study for the drug product stored at 4 °C and at 40 °C, for 24 months.
`In a T-con with the Sponsor, Nov 10, 2015, they agreed to the PMC and provided updated carton
`labels (shown below) with the revised storage/excursion statement.
`
`
`
`Reference ID: 3854243
`
`

`

`
`
`I. Administrative
`
`A. Reviewer’s Signature
`
`Venkateswara R. Pavuluri -A
`-
`(AffillatE)
`
`mswmmmmmnm
`osmtmmmnwm1mmn endanAm-J
`0-2101“ Lu 15:44:1745w
`
`8. Endorsement Block
`
`mmmum;
`o
`.
`mwwsfimmmu-NHSw-‘M
`Julla C. PInto - .mwamzczzm
`MMSJ‘JI “an
`
`Reviewer Name/Date: Venkateswara R. Pavuluri, "1.0.; 11/18/2015
`
`Secondary Reviewer Name/Date: Julia C. Pinto, Ph.D.; 11/18/2015
`
`Reference ID: 3854243
`
`

`

` '-_'
`
`' QUALITY ASSESSMENT — NDA 208411
`
`ASSESSMENT OF MICROBIOLOGY
`
`1. Are the tests and proposed acceptance criteria for microbial burden adequate for
`assuring the microbial quality of the drug product?
`
`Applicant’s Response: Release testing includes microbial enumeration and four
`specified microorganisms including B. cepacia. Microbial release testing is done
`according to USP <61> and <62>.
`
`—mm- Acce - tance Criteria
`Total Aerobic Microbial Count
`FU/mL
`
`Total Combined Yeast/Molds Count
`
`FU/mL
`
`Absent
`
`IR #1 Question (August 2015)
`3. Provide the method verification resultsfor Total Aerobic Microbial Count, Total
`Combined Yeast/Molds Count, specified microorganisms done according to USP
`<61> and USP <62>.
`
`Applicant Response: Method Validation Report M-14-078 [The Method Validation
`Report for Microbial Limits Validation Testing ofNaloxone 40mg/mL Nasal
`Spray (Formula 104401)] was added to 3.2.P.5.3. Method -SOP-00686 was
`provided which describes l) the microbial limits testing procedure via both the plate and
`membrane filtration methods; and 2) pathogen screening using specified growth media.
`
`Product lot #14-60] 12 was tested using the membrane filtration method per USP<61> for
`Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Aspergillus
`brasiliensis and Candida albicans. Pathogen screening per USP <62> was performed for
`Escherichia coli, S. aureus, P. aeruginosa and 3 different strains of Burkholderia
`
`cepacia.
`
`I
`
`Microbiology - NDA 20841 1
`
`Reference ID: 3854243
`
`
`
`

`

`QUALITY ASSESSMENT — NDA 208411
`
`contains material sourced from animals, what documentation is provided to
`assure a low risk of virus or prion contamination (causative agent of TSE)?
`
`Applicant’s Response: There are no excipients of human or animal origin used in the
`formulation of naloxone hydrochloride nasal spray.
`
`Reviewer’g Assessment: Not Applicable
`
`4.
`
`If any of the materials used for the manufacture of the drug substance or drug
`product are of biological origin or derived from biological sources, what drug
`substance/drug product processing steps assure microbiological (viral) safety of
`the component(s) and how are the viral inactivation/clearance capacity of these
`processes validated?
`
`Applicant’s Response: There are no excipients of human or animal origin used in the
`formulation of naloxone hydrochloride nasal spray.
`
`Revimer’g Assessmen : Not Applicable
`
`OVERALL ASSESSMENT AND SIGNATURES: MICROBIOLOGY
`
`
`
`15
`
`Reference ID: 3854243
`
`Microbioloii - NDA 20841 1
`
`

`

`
`
`
`OFFICE OF PHARMACEUTICAL QUALITY
`FILING REVIEW
`
`
`
`
`
`
`
`
`Application #: 208411
`
`
`
`
`
`
`Submissmn Type: Fast Track
`
`
`
`
`Established/Proper Name:
`Naloxone Hydrochloride
`
`
`
`
`
`
`Appllcant: Adapt
`Pharma
`
`
`
`
`Letter Date: July 20, 2015
`
`
`
`
`
`
`
`Dosage Form: lntranasal
`
`
`
`
`
`
`Chemical Type:
`
`
`
`
`
`
`
`Stamp Date: July 20, 2015
`
`
`
`
`
`Strength: 4 mgl100ul
`
`
`
`A. FILING CONCLUSION
`
`
`
`
`
`
`
`-—_
`DOES THE OFFICE OF
`
`
`
`
`
`PHARMACEUTICAL
`
`
`QUALITY RECOMMEND
`
`
`
`THE APPLICATION TO BE
`FILED?
`
`
`
`
`
`
`
`If the application is not fileable
`
`
`
`
`from the product quality
`
`
`
`
`perspective, state the reasons and
`
`
`
`
`
`provide filing comments to be
`
`
`
`
`sent to the Applicant.
`
`
`
`
`Are there any potential review
`
`
`
`
`
`
`issues to be forwarded to the
`
`
`
`
`Applicant, not including any
`
`
`
`filing comments stated above?
`
`
`
`
`
`
`
`
`
`
`
`
`This NDA is filable from the CMC standpoint. No
`
`
`
`
`
`
`
`
`Biopharmaceutics review is needed since the product is a
`
`
`
`
`
`
`spray, and no biowaiver is requested.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`See IR Letter Sent to the Applicant Dated August 21, 2015
`
`
`(Appendix 1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'
`
`,
`
`
`_IM “me”
`
`
`APPLICATION
`
`Product T -e
`
`
`
`
`
`
`
`I:I-_
`New Molecular Entity
`
`
`
`
`
`
`lil-—
`Botanical
`
`
`
`
`
`
`m-
`Naturally-derived Product
`3.
`
`
`
`
`
`
`
`
`Ii.-
`Narrow Therapeutic Index Drug
`4
`
`
`
`
`
`
`Ii.-
`PET Drug
`5
`
`
`
`
`
`Ii.-
`PEPFAR Drug
`6
`
`
`
`
`
`
`
`Sterile Dru ; Product
`Ii.-
`7
`
`
`
`
`8- _m
`
`
`
`
`
`“_“I
`
`
`
`
`
`10- ——I:I-
`
`
`
`
`
`
`Lyophilized product
`x
`11.
`
`
`
`
`
`
`First genericl
`x
`12.
`
`
`
`
`
`
`
`Solid dispersion product
`13.
`X
`
`
`
`
`
`14—“.
`
`
`
`
`
`
`12a}? "—Liposome product
`
`
`
`
`
`
`x
`
`
`
`
`-—-EI
`
`
`
`
`
`mg“:-
`
`
`
`
`
`
`
`
`_-a Fast Track Designation: Intranasal naloxone
`
`
`
`
`
`
`for treatment of opiate overdose.
`
`
`
`
`
`Reference ID: 3854243
`Reference ID: 3854243
`
`
`
`

`

`
`
`
`OFFICE OF PHARMACEUTICAL QUALITY
`FILING REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`23.
`
`
`
`24.
`2 .
`5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Rgglllatory Considerations
`
`
`
`
`
`
`USAN Name Assigned
`I E]
`El
`
`
`
`
`
`
`End of Phase II/Pre-NDA Agreements
`D [I
`
`EIE
`
`
`
`
`
`
`
`(Special Products On-line Tracking System)
`
`
`
`
`Citizen Petition and/or Controlled Correspondence
`
`
`
`
`
`
`Linked to the Application
`
`
`
`
`Elli.
`Com. arability Protocol(s)
`Other
`
`
`
`IIIIII
`
`
`Quality Considerations
`
`
`
`
`
`
`IIIIII—
`Drug Substance Overage
`26.
`
`
`
`
`27- —IIIIII
`
`
`
`
`28-
`- —I:IICI
`
`
`DeSIgn Space —IIIIII
`29-
`
`
`
`
`
`
`
`
`30- —IIIIII
`
`
`
`
`
`
`
`
`31- _IIIIII_
`
`
`
`
`
`
`
`
`
`
`32- _IIIIII
`
`
`
`
`
`
`
`33. —IIIIII
`
`
`
`
`
`
`34- —__IflIII
`
`
`
`
`
`
`
`35.
`Non-compendial Analytical _-:II:.
`
`
`
`
`
`
`Procedures and/0r —m':'
`36.
`
`
`
`
`
`Specifications _IIIIII_
`37-
`
`
`
`
`
`
`38. III—III
`
`
`
`
`
`
`
`
`
`39- —IIIIII
`
`
`
`
`
`40- —IIIIII
`
`
`
`
`
`41. _IIIIII
`
`
`
`
`
`
`
`
`42. —IflIII
`
`
`
`
`
`
`
`
`43. —_I:II:I_
`
`
`
`
`
`44.
`Continuous Manufactunn mm—
`
`
`
`
`
`
`
`Other unique manufacturin_ rocess
`45.
`46.
`Use of Models for Release (IV I VC, dissolution
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`models for real time release).
`
`
`
`
`
`
`
`
`
`
`New delivery system or dosage form
`
`
`
`
`
`
`
`
`Novel BE study designs
`Eli.
`
`
`
`
`
`
`
`New product design
`Eli.
`
`
`
`
`Other
`Eli. ,,
`,
`7,
`
`
`
`
`
`
`
`
`
`Contact Office of Testing and Research foreiew team considerastion
`
`
`
`
`
`
`
`
`2Contact Post Marketing Assessment staff for review team considerations
`
`
`
`8.
`
`UI-b-b-b-CW\]
`
`
`
`2. Is the Quality Overall Summary (QOS) organized
`
`
`
`Reference ID: 3854243
`Reference ID: 3854243
`
`
`C. FILING CONSIDERATIONS
`
`
`
`
`
`
`
`-—-_
`GENERAL/ADMINISTRATIVE
`
`
`
`
`
`
`x
`
`
`
`
`
`x
`
`
`
`
`
`
`
`
`A rolling submission
`
`
`
`1.
`
`
`
`
`
`
`
`
`
`
`Has an environmental assessment report or
`
`
`
`
`categorical exclusion been provided?
`
`
`
`
`
`
`
`
`
`
`
`
`adequately and legible? Is there sufficient
`
`
`
`
`
`
`
`information in the following sections to conduct a
`review?
`
`
`El Drug Substance
`
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`FILING REVIEW
`
`0 Novel Excipients
`0 Regional Information
`0
`Executed Batch Records
`
`.
`
`
`C. FILING CONSIDERATIONS
`
`
`
`
`
`2
`0 Drug Product
`'
`D Appendices
`
`Facilities and Equipment
`0
`0 Adventitious Agents Safety
`
`Evaluation
`
`
`
`
`
`
`
`0 Method Validation Package
`0 Comparability Protocols
`
`:
`
`
`FACILITY INFORMATION
`
`
`
`
`Are drug substance manufacturing sites, drug
`product manufacturing sites, and additional
`manufacturing, packaging and control/testing
`
`
`laboratory sites identified on FDA Form 356h or
`associated continuation sheet? For a naturally-
`
`derived API only, are the facilities responsible for
`critical intermediate or crude API manufacturing, or
`performing upstream steps, specified in the
`
`application? If not, has a justification been
`
`provided for this omission? For each site, does the
`
`application list:
`
`1:! Name of facility,
`
`0 Full address of facility including street, city,
`
`state, country
`
`FEI number for facility (if previously registered
`CI
`
`with FDA)
`
`0 Full name and title, telephone, fax number and
`
`email for on-site contact person.
`
`Is the manufacturing responsibility and
`function identified for each facility, and
`
`DMF number if a - licablc
`
`Is a statement provided that all facilities are ready
`for GMP inspection at the time of submission?
`For BLA:
`
`
`
`
`
`C]
`
`Is a manufacturing schedule provided?
`El
`B Is the schedule feasible to conduct an
`
`For DMF review, are DMF # identified and
`
`authorization letter(s), included US Agent Letter of
`
`
`Authorization provided?
`
` Is the Drug Substance section [3.2.8] organized
`
`adequately and legible? Is there sufficient
`
`
`information in the following sections to conduct a
`review?
`
`
` 0 general information
`
`0 manufacture
`
`
`
`Reference ID: 3854243
`
`

`

`
`
`
`OFFICE OF PHARMACEUTICAL QUALITY
`
`
`
`
`0
`
`
`
`FILING REVIEW
`
`
`
`
`
`
`C. FILING CONSIDERATIONS
`
`
`
`
`
`Includes production data on drug substance
`
`
`
`
`
`
`
`manufactured in the facility intended to be
`
`
`
`
`
`licensed (including pilot facilities) using
`
`