CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`207154Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`Memorandum
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Date:
`From:
`
`February 17, 2016
`Yichun Sun, Ph.D.
`
`Application Technical Lead, Branch V
`Division of New Drug Products II
`Office of New Drug Products
`
`Through:
`
`Moo-Jhong Rhee, Ph.D.
`Chief, Branch V
`
`Division of New Drug Products 11
`Office of New Drug Products
`
`To: CMC Review #1 of NDA 207154
`
`Subject: Final Approval Recommendation for NDA 207154
`
`At the time when the CMC review #1 was written, resolution of issues on Labels and
`Labeling was pending.
`
`Label/Labeling
`On February 11, 2016, the NDA applicant submitted an amendment providing the
`finalized mock up container and carton labels. Additionally, the applicant also agreed to
`all the CMC changes made to the package insert. All the labels/labeling issues are now
`satisfactorily resolved. The review of the CMC sections of the final package insert, and
`mock up container and carton labels was conducted by Dr. Hitesh Shroff is attached
`(Attachment - 1).
`
`Recommendation:
`
`The revised package insert and mock-up container and carton labels are acceptable from
`the CMC perspective. Therefore, from the ONDP’s perspective, this NDA is
`recommended for APPROVAL. An expiration dating period of 24 months is granted for
`the drug product of NDA 207154.
`
`Application Technical Lead’s Assessment and Signature
`
`The NDA is recommended for approval from quality perspective.
`Dlgitally signed blechun
`Sun -5
`DN:c=US, o=U.S.
`
`Yichun Sun, Ph.D.
`
`'
`
`2/ 17/2016
`
`Application Technical Lead, Branch V Yl Ch u n «@3123?
`Division ofNew Drug Products H
`S
`m=YIdIunSun-S-
`un-S
`
`092342192003m.100.1 .1
`=1 300393310
`Date: 2016.02.171421z13
`-OS'00’
`
`

`

`Attachment - 1 (Review of CMC Sections of the Finalized Labeling and
`Labels)
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`2
`
`

`

`I. Package Insert
`
`(a) “Highlights" Section
`
`EIGIIUGIITS Of PWG DTORMATION
`MWdonothdndnllthehlomdon
`needed to use ACZONE‘ Gel. 7.5% salely and
`em. See mu preset-thug bun-ub- [or
`ACZONE‘ Gel. 7.5%.
`
`ACZONE' («lapse-e) Gel. 7.5%. [or topknl use
`new ES. Approval: [’55
`
`—'DOSAGE YORMS AND STRENGTHS—
`Gel 7.5% (3).
`
`(b) “Full Prescribing Information" Section
`
`#3. Dosage Form and Strength
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`Gel. 7.5%. Each gram ofACZONE Gel, 7.5% calmns 75 mg ofdlpsone In In ofi-whne to yellow gel wnh
`suspendedpamdes.
`
`#1 l. Dggcriptjon
`
`ll
`
`DESCRIPTION
`
`ACZONE (dapsone) Gel. 7.5%. contents dapsone. a sulfone. m an aqueous gel base for toptcd dermatology:
`use. ACZONE Gel, 7.5% is an off-white to yellow gel With suspended particles. Chemicmy. dapsone hes an
`en‘puicll {mulls of C13H33N102$ It is a white or slighly yellow-white. ctystnllme powder that has a
`molecular weight of 248.30. Dupsone‘s cheuncal name 15 4~[(4-ammobenzene) sulfonyl] nmhne and its
`shuctunl fomula is:
`
`wOwOm
`
`Each gram of ACZONE Gel, 75%. contains 75 mg of dapsone, USP. in a gel of diethylcne glycol nmoedlyl
`etha. methylpanbea acrylnmde/sodimn auyloyldmmhyl taunte copalymer. Isohexadecane. polysodante 80.
`and punfied water.
`
`

`

`#16 How Supglied/storage and Handling
`
`16
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`ACZONEGdismofi-whitewyeflawgdwnhsspmdedpufidahswmmm”
`conhmingapdypupylmebofliemflnlfighdenmypolyefllylempistm
`
`ACZONE (dlpsone) Gel, 7.5%, is mliedinme buowing sins:
`
`NDC 0023-5206-30
`
`NDC 0023-5206450
`
`NDC 0023-5206-90
`
`30 gram puny
`
`60 gram pulp
`
`90 gram puny)
`
`Storage: Store at 20°C-25°C (68°F-77'F), exclusions pamimd to 15°C-30'C (59°F-86'F) [see USP Candied
`Roan Tamenm]. Placed fi'om fueling.
`
`

`

`QUALITY ASSESSMENT
`
`Recommendation:
`
`This 505(b)(1)NDA is not deemed ready for approval as of this review in its present form per 21
`CFR 314.125(b)(6).
`
`NDA 207154
`
`Review #1
`
`m_—
`
`Ori . inal NDA submission
`
`Amendment
`Amendment
`Amendment
`
`Amendment
`
`4/28/2015
`
`6/1/2015
`
`7/ 15/2015
`7/3 1/2015
`8/2 1/201 5
`
`9/15/2015
`
`9/15/2015
`
`9/30/2015
`
`10/14/2015
`
`All disci - lines of the review team
`
`Biopharmaceutics
`0 1ali microbiolo 3
`
`Dru roduct
`
`Quali Review Team
`DISCIPLINE m BRANCH/DIVISION
`
`API
`
`Products II
`
`“Assessment III
`
`
`
`
`Biopharmaceutics
`
`Vidula Kolhatkar
`
`Regulatory Business Process
`Manager
`
`Maria Cowan
`
`Microbiolo; Assessment
`
`Assessment
`
`Branch lI/Division of
`Bio nharmaceutics
`
`Branch I/Division of Regulatory
`and Business Process
`Mana - ement
`
`Products H
`
`Tobacco 0 I -rations
`
`Products H
`
`

`

`QUALITY ASSESSNIENT
`
`Table of Contents
`
`Table of Contents ..................................................................................................... 2
`
`Quality Review Data Sheet......................................................................................3
`
`Executive Summary ................................................................................................. 5
`
`Primary Quality Review ........................................................................................ l0
`
`ASSESSMENT OF THE DRUG SUBSTANCE ...................................................................... 10
`
`2.3.5
`
`DRUG SUBSTANCE ........................................................................................ 10
`
`ASSESSMENT OF THE DRUG PRODUCT........................................................................... l7
`
`2.3.P
`
`DRUG PRODUCT ............................................................................................ 17
`
`R2
`
`Comparability Protocols ...................................................................................42
`
`ASSESSMENT OF THE PROCESS......................................................................................... 45
`
`2.3.P
`
`DRUG PRODUCT ............................................................................................45
`
`R2
`
`Comparability Protocols ...................................................................................64
`
`ASSESSMENT OF THE FACILITIES .................................................................................... 67
`
`2.3.8
`
`2.3.P
`
`DRUG SUBSTANCE ........................................................................................67
`
`DRUG PRODUCT ............................................................................................68
`
`ASSESSMENT OF THE BIOPHARMACUETICS ................................................................ 74
`
`ASSESSMENT OF MICROBIOLOGY ................................................................................... 82
`
`2.3.P.7 Container/Closure System .................................................................................84
`
`A
`
`APPENDICES ................................................................................................................ 85
`
`ASSESSMENT OF ENVIRONNIENTAL ANALYSIS ........................................................... 87
`
`1.
`
`II.
`
`List of Deficiencies To Be Communicated .................................................................. 100
`
`Attachments ................................................................................................................... 102
`
`

`

` """""‘
`QUALITY ASSESSMENT
`7
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS:
`
`1 Adequate, Adequate with Information Request, Deficient, or N/A (There is enough data in the
`application, therefore the DMF did not need to be reviewed)
`
`Adequate
`
`l4-DEC-2015
`
`Reviewed by
`Dr. Hitesh N.
`Shroff
`
`
`. lication.
`
`B. Other Documents: IND, RLD, or sister applications
`
`m APPLICATION NUMBER
`EOPZ meeting minutes
`IND 054440
`
`NDA 21794
`
`DESCRIPTION
`Discussion of the development
`plan for dapsone gel, 7.5% for the
`treatment of acne Vul_ .
`'s.
`Cements and recommendations
`
`regarding the proposed dosage
`
`Providing the location of
`chemistry, manufacturing, and
`controls informtion previously
`submitted to NDA 21794 for
`
`ACZONE (dapsone) Ge], 5% and
`specifically referenced by this
`.
`
`

`

`QUALITY ASSESSNIENT
`
`2. CONSULTS:
`
`smvs
`
`um
`
`/A ——
`
`N/A
`
`

`

`
`“'""""
`QUALITY ASSESSMENT
`
`I.
`
`Recommendations
`
`Executive Summary
`
`Recommendation and Conclusion on Approvability
`The applicant of this NDA has provided sufficient CMC information to assure the
`identity, strength, purity, and quality of the drug substance and drug product.
`
`The facility review team from the Oflice of Process and Facility has issued an
`“Approval” recommendation for the facilities involved in this application (See the
`Attachment B).
`
`However, the issues on labels/labeling are not completely resolved at this time.
`
`Therefore, from the OPQ perspective, this NDA is not ready for approval in its present
`form per 21 CFR 314.125(b)(6) until the aforementioned issues are satisfactorily resolved
`(See the List of Deficiencies on pp. 100-101).
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`N/A
`
`Summary of Quality Assessments
`
`Drug Substance [USAN Name] Quality Summary
`The drug substance/active pharmaceutical ingredient (APl) used in the drug product,
`(dapsone gel), is dapsone. The drug substance is chemically produced. The chemical
`name of dapsone is: 4-[(4-aminobenzene)sulfonyl]aniline. It has the following structural
`formula:
`
`WQQ
`
`Dapsone is a white or slightly yellow-white, crystalline powder that has an empirical
`formula of C12H12N2028 and a molecular weight of 248.30. Dapsone melts in the
`temperature range of 175 — 181°C. Dapsone is very slightly soluble in water, freely
`soluble in acetone, sparingly soluble in alcohol, and dissolves freely in dilute mineral
`acids. The amine groups on the aminobenzene rings have calculated pKal of 0.5 and
`calculated Ka of 1.2 res ectivel
`
`
`.
`
`

`

`QUALITY ASSESSNHENT
`
`bottle with a hlili densii mlethylene piston. Additionally, 3 g professional samples
`
`laminated tube are also available.
`
`packaged in an
`
`B. Drug Product [Established Name] Quality Summary
`The drug product, ACZONE (dapsone) Gel, is an off-white to yellow gel with suspended
`dapsone particles. The strength of dapsone gel is 7.5% (w/w). Dapsone is a sulfone
`indicated for the topical treatment of acne vulgaris in patients 12 years of age and older.
`Each gram of ACZONE contains 75 mg of dapsone in a gel of diethylene glycol
`monoethyl ether, methylparaben, acrylamide/sodium acryloyldimethyl taurate copolymer,
`isohexadecane, polysorbate 80, and purified water.
`ACZONE (dapsone) Gel, 7.5%, is packaged in an airless pump container closure system
`in 3 different sizes (30 g, 60 g and 90 g). The airless pump contains a polypropylene
`
`The eepeeee eel ieeeeeeeeeey—
`
`

`

`QUALITY ASSESSMENT
`
`The identity, strength, purity including microbial limits, and quality of the drug product
`are deemed assured by the drug product specification. An in vitro release test (IVRT) of
`dapsone gel has been developed but not fully validated. The facility review team from
`the Office of Process and Facilities has provided an Overall Acceptable recommendation
`for the facilities involved in the manufacture and test of the drug substance and drug
`product. The expiration dating period of 24 months is recommended for the drug product
`when stored at controlled room temperature based on the 12-month long—term and 6-
`month accelerated stability data obtained from 3 registration batches of the drug product.
`
`C. Summary of Drug Product Intended Use
`
`nnNa-nenmsoa
`
`Nonrrop-ietary NameMvn-ga
`
`NonrrowietawNa-neom-emmnmg
`
`Proposed Indication(s) including Intended Patient Dapsone gel is indicated for the
`P°Pulafi°n
`topical treatment of acne vulgaris in
`.atients 12 ears of a - e and older.
`
`
`
`Maximum Daily Dose
`
`Alternative Methods of Administration
`
`Approximately a pea—sized amount of
`Aczone gel, 7.5%, in a thin layer to
`the entire face once daily or other
`affected areas once daily.
`N/A
`
`D. Biopharmaceutics Considerations
`1. BCS Classification:
`
`0 Drug Substance: N/A
`0 Drug Product: N/A
`
`2. Biowaivers/Biostudies
`
`o Biowaiver Requests: N/A
`0 PK studies: N/A
`
`0
`
`0
`
`IVIVC: N/A
`
`IVRT:
`
`An IVRT method has been developed by the NDA applicant. However, the
`IVRT method has not been fully validated. The applicant proposed to
`validate the IVRT method before it can be used to test to-be-marketed
`
`batches of the gel. Additionally, acceptance criteria of the IVRT method
`will be set until sufficient data with validation lots (t = 0 and stability data)
`are available. The Agency agrees with the applicant’s approach for
`establishing in vitro release specifications. The following comments were
`conveyed to the applicant in a general advice letter on December 23, 2015:
`
`0
`
`Submit the IVRT method validation report, and provide your
`proposed in vitro release acceptance criteria based on the data
`
`

`

`QUALITY ASSESSMENT
`
`from at least 6 production batches, to the Agency at your earliest
`convenience, but by the first Annual Report at the latest.
`
`E. Novel Approaches
`N/A
`
`F. Any Special Product Quality Labeling Recommendations
`Protect from freezing.
`
`G. Life Cycle Knowledge Information (see Attachment A)
`
`

`

`
`
`OVERALL ASSESSMENT AND SIGNATURES: EXECUTIVE SUNIMARY
`
`
`
`

`

`
`
`ASSESSKIENT OF THE BIOPHARMACUETICS
`
`22. Are the in-vitro dissolution test and acceptance criteria adequatefor assuring quality
`control and consistent bioavailability ofthe drugproduct?
`
`In the 74-day letter, the Agency recommended that the applicant develop an in vitro
`release test (IVRT) methodology and propose in vitro release acceptance criteria (range)
`for the proposed drug product to be used at release and during stability as a quality
`control parameter.
`
`Applicant’s Response: On July 14, 2015 a teleconference was held between the Agency and the
`applicant to clarify the recommendation received in the 30 June 2015 Filing Communication
`letter. During the teleconference, the following items were agreed upon:
`
`0 Allergan committed to develop and validate an IVRT method as recommended by the
`Agency.
`
`0 Allergan agreed to provide a status update on method development and validation by the end
`of September 2015.
`
`o
`
`The Agency agreed that if there are difficulties with completing the validation or justifying
`the specifications, the method validation and specifications can be set as a post-marketing
`commitment.
`
`The applicant submitted a status report about in vitro release method development on September
`30, 2015 as agreed at the teleconference.
`
`
`
`

`

`
`
`

`

`QUALITY ASSESSNIENT
`
`23. Are the changes in theformulation, manufacturingprocess, manufacturing sites during
`the development appropriately bridged to the commercialproduct?
`
`The commercial formulation was used in two pivotal Phase 3 studies and four Phase 1
`studies.
`
`Applicant’s Response: N/A
`
`Reviewer’s Assessment: NIA
`
`

`

`QUALITY ASSESSMENT
`
`OVERALL ASSESSMENT AND SIGNATURES: BIOPHARMACUETIC S
`
`Reviewer’s Assessment and Si nature: IVRT method is acceptable.
`The applicant has stated that the IVRT method will be validated prior to testing of to-be-
`
`marketed batches and specifications will be included as ‘report’ until sufficient data with
`
`validation lots (t = 0 and stability) are available. The Agency agrees with the applicant’s
`approach for establishing in vitro release specifications. The following comments were
`conveyed to the applicant in a general advice letter on December 23, 2015:
`
`Submit the IVRT method validation report, and provide your proposed in vitro release
`acceptance criteria based on the data from at least 6 production batches, to the Agency at your
`
`earliest convenience, but by the first Annual Report at the latest.
`
`Vid U l a R
`
`.
`
`33:12:13???“ byV'du'aR‘
`
`
`
`Reviewer’s Signature
`
`Vidula Kolhatkar, Ph.D.
`B
`h H
`
`”“1“
`Division of Biopharmaceutics/ONDP
`01/05/2016
`
`DN=C=U5,0=U5-Govemment.
`ou=HHS, ou=FDA, ou=People,
`.
`.
`.
`.
`. =
`Kol hatka r -S Zaififlfffiififléf’fiolfififs
`Date: 2016.01 .11 11:29:13 -05'00‘
`
`Secondau Review Comments and Concurrence:
`
`I have reviewed the Biopharmaceutics Assessment, and I concur with the Reviewer’s
`assessment and comments to convey to the Applicant.
`
`Supervisor’s Signature
`.
`Kelly Kitchens, Ph.D.
`QAL’ Branch 11
`Division of Biopharmaceutics/ONDP
`01/05/2016
`
`Ke I Iy M
`KltC h e n S _ S
`
`Digitally signed by Kelly M. Kitchens -5
`DN: c=US, o=U.S. Government, ou=HHS,
`
`83:23:,1°gufozgooglibo 1 1 2000336574
`ch=.Kelly-M. Kitchens -5'
`I _
`Date: 2016.01.11 11:31:55 —OS'00'
`
`'
`
`

`

`
`"""""
`QUALITY ASSESSMENT
`
`,
`
`ASSESSMENT OF NHCROBIOLOGY
`
`24. Are the tests andproposed acceptance criteriafor microbial burden adequatefor
`assuring the microbial quality ofthe drugproduct?
`
`Applicant’s Response:
`ACZONE (dapsone) Gel, 7.5% is a gel for cutaneous use. This is an aqueous, multiple dose
`product.
`
`The drug product is tested for Microbial Limits at release using a method consistent with USP
`Chapter <61> (Microbiological Examination ofNon-sterile Products: Microbial Enumeration Tests)
`and <62> (Microbiological Examination ofNon-sterile Products: Tests for Specified
`Microorganisms). The Microbial Limits acceptance criteria are consistent with USP Chapter
`<111 1> (Microbiological Examination ofNon-sterile Products: Acceptance Criteria for
`Pharmaceutical Preparations and Substances for Pharmaceutical Use) and comply with the agency’s
`request that the drug product should not contain Burkholderia cepacia. These limits include a total
`combined yeasts and molds cOImt (TYMC) ofWT. CFU/g, total aerobic microbial count
`(TAMC) ofNMI'I CFU/g, and the absence ofStaphylococcus aureus, Pseudomonas aeruginosa,
`and B. cepacia.
`
`Applicant states that the test for B. cepacia is based on principles derived from USP <62>. The
`test method requires a 1:100 dilution (for TAMC) and 1:10 dilution (for TYMC) of the test
`material in tryptic soy broth with 4% polysorbate 20 and 0.5% lecithin. If any organisms are
`detected, the identity of the organism will be determined. The submission dated 04/28/2015 did
`not provide validation studies to document that the test method can detect B. cepacia in the drug
`product.
`
`The following information request was sent to the firm on 06/30/2015:
`
`Section 3. 2.P. 5.2 ofthe application outlines the testfor the absence ofBurkholderia cepacia in
`the drugproduct. Provide thefollowing:
`a. A detailed description ofthe test method that specifies the growth conditions (i.e., growth
`medium, incubation time and temperature).
`
`In their response dated 07/31/2015, the applicant described the following test method
`
`
`
`The following information was requested from the firm on 06/30/2015:
`
`

`

`QUALITY ASSESSMENT
`
`The applicant responded to the request on 07/31/2015 with the following information.
`
`B. cepacia ATCC 25416 used for inoculation of the test group and control group is prepared by
`the following procedure.
`
`b. Validation studies to confirm that the test method is suitablefor detection ofB. cepacia in the
`drugproduct. Include pre-incubation conditionsfor the B. cepacia test strain and enumeration
`ofinoculated organisms.
`
`7.5%. The results are summarized in Table I copied from the submission.
`
`Following the above procedure, method suitability was demonstrated using 3 lots of Aczone
`
`

`

`QUALITY ASSESSMENT
`
` Table l Method Suitablity using 3 Lot ofAczone 7.5%
`
`
`Test Sample
`Selective
`Test Group
`Positive
`Negative
`Viability Control,
`
`Lotti
`
`Media
`
`(Product)
`
`('ontt'ol
`
`(‘ontrol
`
`Average # of (‘F1'
`
`RNA-1C ‘MacConkey
`
`("yrotvth
`
`' Growth
`
`H'lL-C
`
`A Muct‘onkc)‘
`
`Gromh
`
`‘ Growth
`
`l-‘llK-C
`
`‘Mact‘oukcy
`
`Growth
`
`‘ Growth
`
`Nogrou‘lli
`
`Nogromlt
`
`No growth
`
`The microbial limits test methods for TYMC, TAMC, and absence ofStaphylococcus aureus and
`Pseudomonas aeruginosa provided in the submission dated 04/28/2015 were verified to be
`appropriate for use with the drug product following procedures consistent with those in USP
`Chapter <61> and <62>.
`
`The product is tested for preservative content at release and as part of the stability program. The
`lower limit of the specification for preservative content is -% w/w
`(no). Antimicrobial efl'ectiveness testing of a lot formulated with % w/w
`one was performed using methods described in USP <51> and al ots met USP criteria
`for Category 2 products.
`
`The drug product will also be tested for microbial limits as part of the post-approval stability
`protocol.
`
`Reviewer’s Assessment:
`
`recommended for approval from the standpoint of product quality microbiology.
`
`The microbial limits specification for ACZONE (dapsone) Gel, 7.5% is acceptable
`from a Product Quality Microbiology perspective. Therefore, this submission is
`
`2.3.P.7
`
`Container/Closure System
`
`25. Is the proposed container/closure systemfor the drug product validated tofimction as a
`barrier to microbial ingress? What is the container/closure design space and change
`controlprogram in terms ofvalidation?
`
`Applicant’s Response: N/A
`
`Reviewer’s Assessment: NIA
`
`

`

`QUALITY ASSESSNIENT
`
`A
`
`APPENDICES
`
`A.2
`
`Adventitious Agents Safety Evaluation
`
`26. Are any materials usedfor the manufacture ofthe drug substance or drugproduct of
`biological origin or derivedfrom biological sources? Ifthe drug product contains
`material sourcedfrom animals, what documentation is provided to assure a low risk of
`virus or prion contamination (causative agent of TSE) ?
`
`Applicant’s Response: N/A
`
`Reviewer’s Assessment: N/A
`
`27. Ifany ofthe materials usedfor the manufacture ofthe drug substance or drug product
`are ofbiological origin or derivedfrom biological sources, what drug substance/drug
`productprocessing steps assure microbiological (viral) safety ofthe component(s) and
`how are the viral inactivation/clearance capacity ofthese processes validated?
`
`Applicant’s Response: N/A
`
`Reviewer’s Assessment: N/A
`
`

`

`
`
`OVERALL ASSESSNIENT AND SIGNATURES: NIICROBIOLOGY
`
`
`
`

`

`
`
`ASSESSlWENT OF EN V IRONlVIENTAL ANALYSIS
`
`28. Is the applicant’s claimfor categorical exclusion acceptable?
`
`29. Is the applicant ’s Environmental Assessment adequatefor approval ofthe application?
`
`Applicant’s Response:
`The action increases the use of active moiety, but the estimated concentration of the substance at
`the point of entry into the aquatic environment will be below 1 part per billion. No extraordinary
`circumstances exist that would significantly affect the quality of the human environment as a
`result of the proposed action.
`
`

`

`
`
`

`

`QUALITY ASSESSMENT
`
`A. Labeling & Package Insert
`
`WM:
`
`Immediate container labels
`
`Review of Common Technical Document-Quality (CDd-Q) Module 1
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`(II) (4)
`
`Comments on the Information Provided in
`NBA
`
`Proprietary name. established name (font The drug name is presented correctly.
`size and prominence (21 CFR
`Satisfactory
`201 . 10(g)(2))
`
`Dosage strength (2 lCFR 201.10(d)(l):
`21.CFR 201.100 t 4
`
`Displayed as 7.5 %
`Satisfacto
`
`Net contents (21 CFR 201.51(a))
`
`“Rx only” displayed prominently on the
`main anel
`
`Net content properly displayed as 30 g, 60 g
`and 90 g
`Satisfactory
`The statement displayed.
`Satisfacto
`
`
`
`207.35 u
`
`3 i
`
`201.17
`
`Satisfacto
`
`N‘“ “W
`Not Satisfactory
`
`Storage condition is not displayed properly
`Not Satisfactory
`
`Name of manufacturer/distributor
`
`Not Satisfactory
`The names of manufacturer and distributor are
`
`List of Ingredients
`
`displayed correctly.
`Satisfacto
`
`Incorrect ingredients are listed.
`Not Satisfactory
`
`Evaluation: Not adequate. The 30 g, 60 g and 90 g pump labels should be revised to include
`the following information:
`0 Display “Lot” and “Exp:”
`0 Display a barcode
`
`0 Add the following statement in the storage condition description
`“[See USP Controlled Room Temperature]”
`0 List ingredients as shown below:
`“Each gram of gel contains 75 mg of dapsone, diethylene glycol monoethyl
`ether, methyl paraben, acrylamide/sodium ac1yloyldimethyl taurate
`copolymer, isohexadecane, polysorbate 80 and purified water.”
`
`The 3 g sample tube labels should be revised to include the following
`information:
`
`0 Display “Lot:” and “Exp:”
`
`0 Add the following statement in the storage condition description
`“[See USP Controlled Room Temperature]”
`
`2 Page(s) of Drafi Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`“ Cements on the Information Provided in NBA
`Proprietary name. established name (font
`Proprietary name and established name are correctly
`size, prominence) (FD&C Act
`described.
`502(e)(l)(A)(i). FD&C Act 502(c)(l)(B). 21 Satisfactory
`CFR 201 .10(g)(2))
`
`Dosage strength (21CFR 201.10(d)(1),
`21CFR 201.100(b)(4))
`
`Displayed as 7.5 %
`Satisfactory
`
`201.51 a
`
`anel 21 CFR 201.100 t
`
`1
`
`201.17 and 21 CFR 201.18
`
`Storage conditions
`
`Satisfacto
`
`Satisfacto
`
`Salisfacto
`
`Storage condition is not described adequately on the
`carton.
`Not Satisfacto
`
`Satisfacto
`
`
`
`3 i
`207.35 t
`Manufacturer/distributor's name
`
`Satisfacto
`The names of manufacturer and distributor are
`
`21CFR201.1(a)
`
`The list of inactive ingredients. 21CFR
`201.10(a). if not oral dosage form; and
`quantitative ingredient information. if
`tarenteral in'ection. 21CFR 201.100 -
`
`5 iii
`
`displayed correctly.
`Satisfacto
`
`Incorrect ingredients are listed.
`Not Satisfactory
`
`“See package insert for dosage information” This statement is correctly displayed as “See
`(21 CFR 201.55)
`package insert for dosage information"
`Satisfacto
`
`OTC but 0 ttional for Rx dru- s
`
`Satisfacto
`
`Evaluation: Not Adequate.
`
`Satisfacto
`
`The 8 x 3 g sample tubes, 30 g, 60 g and 90 g carton labels should be revised to include
`the following information:
`
`Add the following statement in the storage condition description
`0
`“[See USP Controlled Room Temperature]”
`
`List ingredients as shown below:
`0
`“Each gram of gel contains 75 mg of dapsone, diethylene glycol monoethyl ether,
`methyl paraben, acrylamide/sodium ac1yloyldimethyl taurate copolymer,
`isohexadecane, polysorbate 80 and purified water.”
`
`The 8 x 3 g sample tube carton labels should be revised to include the following
`information:
`
`

`

`QUALITY ASSESSMENT
`
`0
`
`Display “Lot:” and “Expz”
`
`Labeling Review
`
`The following is a summary of the labeling review.
`
`1. Package Insert
`
`(a) “Highlights” Section (21CFR 201.57(a))
`HIGHLIGHIS or PRESCRIBLVG INFORMATION
`These highlights do not include all the information
`needed to use ACZONE‘ Gel, 7.5% safely and
`etfectirely. See full prescribing information for
`A( 20312" Gel, 7.5%.
`
`ACZONE" (dapsone) Gel. 7.5%
`For topical use only
`Initial I’.S. Approval: 1955
`
`
`
`DOSAGE EORMS AND SIRESCIHS———-
`Gel, 7 5% Each gram of ACZONE“ Gel. 7 5% contains
`75 mg of dapsone in an off-white to yellow gel (3).
`
`Information
`Provided in NBA
`
`Reviewer’s Assessment
`
`Product title, Dru_ name 201.57 a 2
`
`Proprietary name and ‘ CZONE (dapsone)
`established name
`
`. e drug product title is described conectly.
`
`Dosage form. route
`_
`'
`.
`of adnnmstration
`
`-
`Controlleddrug
`substance symbol (1f
`applicable)
`
`'
`
`/A
`
`\I osage form is displayed correctly. The route of
`
`». dministration is not displayed.
`‘ ot Satisfactory
`
`Dosa_e Forms and Stren_ hs 201.57 a 8
`
`A concise sunmiary
`of dosage forms and
`strengths
`
`- l. 7.5%. Each gram The dosage form and strength are described correctly.
`O f ACZONE® Gel.
`However the description should be deleted.
`.5% contains
`’
`
`Satisfactory
`
`75 mg 0f (131350116 in
`off-white to yellow gel
`
`Not Satisfactory
`
`The product is not scored.
`
`Whether the
`drugproduct is
`scored (If the
`product is not
`scored, do not say
`
`Evaluation: Not adequate. This section should be revised as follows:
`0 Display the drug product title as shown below:
`ACZONE (dapsone) gel, for topical use
`0 Delete the following statement:
`
`

`

`QUALITY ASSESSMENT
`
`Each gram of ACZONE Gel, 7.5% contains 75 mg of dapsone in an off-white to
`yellow gel
`
`# 3: Dosage Forms and Strengths ngCFR 201.57gcu4n
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`Gel, 7.5% Each gram of ACZOXE' Gel, 7.5% contains 75 mg of dapsone in an off-white to yellow gel.
`
`_ Information ProvidedinNDA
`. vailable dosage forms
`
`SIfiSfICtol'y
`
`Strengths: in metric system
`
`Description ofthe identifying
`characteristics ofthe dosage
`forms, including shape. color,
`coating. scoring. and
`imprinting. when applicable.
`
`.ch gram of ACZONE Gel, 7.5%
`. ntains 75 mg of dapsone in an ofl-
`hite yellow gel.
`
`The dosage fonn'is dmbed
`correctly.
`
`Evaluation: Not adequate. This section should be revised as follows:
`0 Revise the dosage form description as shown below:
`
`Each gram of ACZONE Gel, 7.5% contains 75 mg of dapsone in an off-white to
`yellow gel with suspended particles.
`
`#11: Description (21CFR 201.57tcn 12“
`
`l 1
`
`DESCRIPTION
`
`ACZONE: GeL 7.5%. contains dapsone a sulfone. in an aqueous gel base for topical denmtologic use.
`ACZONE Gel 75% is an off-white to yellou gel with suspended drug particles Chemically dapsone has an
`empirical fornnla ofC1~H1iN~O~S It is a white or slightly yellow-white crystalline powder that Ins a
`molecular weight of 248. Dapsone‘s chemical name is 4,4‘-diaminodiphenylsulfone and its structural fmmula
`15.
`
`Moscow:
`
`Each gram of ACZONE8 Gel. 75%. contains 75 mg of dapsone. USP, in a gel of; diethylene glycol monoethyl
`ether: metliylparahen: acrylamide’sodium acryloyldimethyl Inmate copolymer, isohexadecane; polysoibate 80:
`and purified water.
`
`_ Information Provided in NBA
`Proprietary name and established
`ACZONE Gel. 7.5%
`name
`
`Not Satisfactory
`
`The proprietary name is
`correct, however, the
`established name is not
`
`displayed.
`
`

`

`QUALITY ASSESSNIENT
`
`Dosage form and route of
`administration
`
`Gel . for topical dermatologic use
`
`Dosage form and route of
`Administration are
`
`displayed correctly.
`
`Satisfactory
`
`Not applicable
`
`Not applicable
`
`Active moiety expression of
`strength with equivalence statement
`for salt (if applicable)
`Information for inactive
`u 'ethylene glycol monoethyl
`Inactive ingredient information
`ingredients is provided
`ther; methylparaben;
`(quantitative, if injectables
`2 l CFRZO 1 . 100(b)(5)(iii)), listed by . crylamide/sodium acryloyldimethyl correctly.
`USP/NF names.
`aurate copolymer: isohexadecane;
`- . lysorbate 80:
`w. d purified water.
`
`I ot applicable
`
`Not applicable
`
`Satisfactory
`
`
`
`Statement of being sterile (if
`applicable)
`Pharmacological/ therapeutic class
`
`Chemical name. structural formula. Chemical Name:
`molecular Weight
`A .4"-dianfinodiphenylsulfone
`
`Molecular formula:
`
`C121'1121‘1202S
`
`Molecular weight: 248
`
`molecular structure is:
`
`wow»
`
`The Pharmacological/
`therapeutic class displayed
`correctly
`
`Satisfactory
`
`The chemical name is
`not the HJPAC name.
`The MW is not precise.
`
`.
`Not Satisfactory
`
`If radioactive. statement of
`important nuclear characteristics.
`Other important chemical or
`physical properties (such as pKa.
`solubility, or pH)
`
`An off-white to yellow gel with
`suspended drug particles.
`
`(Dapsone) It is a white or slightly
`yellow-white. crystalline powder.
`
`Not applicable
`
`Evaluation: No adequate. This section should be revised as follows:
`
`0 Revise the drug product title as shown below:
`ACZONE (dapsone) gel, 7.5%
`0 Replace the chemical name with the following IUPAC name:
`4-[(4-aminobenzene)sulfonyl] aniline
`o The molecular weight of dapsone should be revised to “248.30”
`
`

`

`QUALITY ASSESSMENT
`
`#16: How Supplied/Storage and Handling (21CFR 201.57tclj 17)!
`
`HQ“' SI'PPLIIDISTORAGE AND HANDLING
`16
`ACZONEa (dapsone) Gel. 7.5%. is supplied In the following Sizes:
`NDC 0023-5206—30
`30 gram airless pump polypropylene bottles
`
`NDC 0023-5206-60
`60 gram airless pump polypropylene bottles
`
`NDC 002 3-5106-90
`
`90 gram airless pump polypropylene bottles
`
`Storage, Store at controlled room temperature. 20°-25°C (68°-77°F). exclusions penmtted to lS°—30°C (59°—
`86'F). Protect from freeing.
`
`_ Information Provided in NBA
`Strength of dosage form
`
`Available units (e.g.. bottles of 30 g. 60 g and 90 g airless pump
`100 tablets)
`propylene bottles
`
`This information should be
`revised
`
`Identification of dosage forms. I ot provided
`e. g.. shape, color. coating.
`scoring. imprinting. NDC
`mnnber
`
`Not Satisfactory
`
`This information is not
`provided.
`
`Not Satisfactory
`
`Not Satisfactory
`
`Special handling (e.g.. protect
`from light. do not freeze)
`Stora e conditions
`g
`
`I' otect from freezing
`
`tore at controlled room temperature.
`v 0°-25°C (68°-77°F). excursions
`permitted to 15°-30°C (59°-
`
`Special storage condition is
`provided.
`'
`'
`Information not prowded
`WWW-
`
`Evaluation: Not adequate. How Supplied and Handling section should be revised as follows:
`0 The following drug product and container closure description should be added
`ACZONE gel is an off-white to yellow gel with suspended particles It is supplied in
`airless pumps containing polypropylene bottles with high de