CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
` 209089Orig1s000
` 209090Orig1s000
`
`PRODUCT QUALITY REVIEW(S)
`
`
`

`

`QUALITY ASSESSMENT
`
`Recommendation: APPROVAL
`
`NDA 209089
`
`Review # 1
`
`Drug Name/Dosage Form
`
`Xyzal® Allergy 24 HR
`Levocetirizine Dih drochloride Tablets
`
`RonteofAdmlnistution
`RxIOTCDis-wsed
`
`OTC
`
`N/A
`
`Applicant
`
`US a n if‘ . ulicable
`
`UCB, Inc.
`1950 Lake Park Drive
`
`Sm“; Geo _'a 30080
`
`
`
`Amendment
`
`06—Ma -201 6
`
`ONDP
`
`
`Quality Review Team
`
`DISCIPLINE
`REVIEWER
`BRANCH/DIVISION
`
`Drug Substance
`
`Sukhama a Bain, Ph.D.
`
`:u : _Cl'
`
`ONDP/DNDP-II/ Branch VI
`ONDP/DNDP-III BrmchVI
`
`OPF/DPAII/BranchVI
`OPF/DPAIl/BranchVI
`OPF/DIA/BB
`ONDP/DB/BBH
`
`ORA/OMl’TOIDMPrPOIMDTP
`
`ONDP/DNDP-II/ BranchVI
`NA
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`man—m:—
`
`NDA—209089
`
`Executive Summary]
`
`

`

`QUALITY ASSESSMENT
`
`REFERENCED
`
`REVIEW
`COMPLETED
`
`(b) (”—Typc-III
`
`Type -III
`
`W
`
`Type-III
`
`Type-III
`
`Type-III
`
`
`
`Sufficient data in the
`application.
`
`The DMF and the
`components have
`been reviewed in
`
`detail by Dr. Jean
`Salemme, PhD. (l3-
`Feb-2003), and were
`found to be ade te.
`
`indication.
`
`.J-lication.
`
`Sufficient data in the
`application.
`
`Sufficient data in the
`2 y u licafion.
`Sufficient data in the
`application.
`
`0” (4) Adequate
`
`Adequate
`
`13-Feb-2003
`
`N/A
`
`N/A
`
`N/A
`
`‘ 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)
`
`B. Other Documents: 1ND, RLD, or sister applications
`
`APPLICATIONm— mmm
`
`
`
`—m__
`
`2. CONSULTS:
`
`DISCIPLINE
`
`STATUS
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`Clinical
`
`—————
`Pharmacology/'1‘oxicology
`—
`CDRH
`—
`
`NBA-209089
`
`Executive Summary2
`
`

`

`QUALITY ASSESSMENT
`
`Table of Contents
`
`Table of Contents ............................................................................................ 3
`
`Quality Review Data Sheet .........................................Executive summary 1-2
`
`Executive Summary ........................................
`
`Executive summary 4-9
`
`ASSESSMENT OF THE DRUG SUBSTANCE———---------------Drug Product 10
`
`2.3.8
`
`DRUG SUBSTANCE———-———-———————Drug Product 10-21
`
`ASSESSMENT OF THE DRUG PRODUCT------------------------Drug Product 22
`
`2.3.P
`
`DRUG PRODUCT-----------------------------------------Drug Product 22-33
`
`ASSESSMENT OF THE PROCESS-------------——--—-——Process review 34
`
`2.3.P
`
`DRUG PRODUCT .................................................Process review 34-42
`
`ASSESSMENT OF THE BIOPHARMACUETICS ........................Biopharm Review 43-49
`
`ASSESSMENT OF THE FACILITIES .........................................................FR Page 50-60
`2.3.S
`DRUG SUBSTANCE ........................................................FR Page 51-53
`
`2.3.P
`
`DRUG PRODUCT ...............................................................FR Page 53—59
`
`ASSESSMENT OF MICROBIOLOGY ...............................N/A (see process review)
`
`Container/Closure System .......................Drug product review Page 28-29
`
`ASSESSMENT OF ENVIRONMENTAL ANALYSIS .............................N/A
`
`Labeling & Package Insert........................................................Drug Product Labeling 61-66
`
`NBA-209089
`
`Executive Summary3
`
`

`

`QUALITY ASSESSMENT
`
`Executive Summary (NDA-209089)
`Recommendations
`
`1.
`
`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, quality
`biopharmaceutics, process 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
`36 months under controlled room temperature storage conditions.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable: N/A
`
`Summary of Quality Assessments;
`II.
`Drug Substance and drug product information is referred to Applicant’s previOusly
`approved NDA 22-064. The current NDA (NDA-209089) is from the same applicant,
`and the only difference is that the non-prescription tablet will have a debossed tablet logo
`instead of a printed tablet logo and will not use any printing ink. Quality information for
`the drug substance and drug product 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: ®-[2-[4-[(4-Chlorophenyl)phenylmethy1]-1-
`piperazinyl]ethoxy] acetic Acid Dihydrochloride.
`Levocetirizine Dihydrochloride
`17011111113: (Cz1H25C1N2032HC1).
`CAS Number 130018-87-0
`
`"'"N
`
`N
`
`CH
`
`' 2H0
`
`O
`
`Cl
`
`O O
`
`MW= 461.82
`
`The currently approved suppliers of levocetirizine dihydrochloride drug substance are
`UCB Farchim S.A. Bulle, Switzerland. Currently, other drug substance manufacturing
`sites
`(”ML
`W" are inactive. Specifications for the drug substance
`includes critical tests for Identification (Levocetirizine dihydrochloride: conforms to {'3
`n.‘ "-
`“one Related impurities by
`(”‘4’
`
`NDA-209089
`
`Executive Summary4
`
`

`

`QUALITY ASSESSMENT
`
`(b) (4)
`
`(no)
`levocetirin'ne dihvdrochlorideis“,stored at
`and a
`re-test periodis assigned based on stability data from
`long term and accelerated storage conditions.
`
`A. Drug Product [Established Name] Quality Summary
`1. Strength: 5 mg
`
`2. Description/Commercial Image:
`The proposed OTC drug product, Levoceu'rizine Dihydrochloride Tablets, 5 mg, are
`white to off—white, film-coated, oval—shaped scored tablets, debossed “X X” logo on one
`side of the tablet, with one “X” on each side of the score. The theoretical tablet weight18
`approximately
`0”“) based on a yield corresponding to (may).
`3. Summary of Product Design
`This application proposes that the only change in the composition of the drug product,
`going from prescription (approved NDA 022064) to non-prescription (presently
`submitted NDA 209089), is the
`“M"; Thus, no significant
`pharmaceutical development work is submitted on the proposed OTC product.
`
`Pnnlod Tablet Loco
`
`0'!»st Tablet Logo
`
`'-
`
`The manufacturing process
`uniformity of the
`W" Dissolution comparison between the printed tablets, debossed tablets and split
`debossed tablets are performed and the values are similar. Dissolution met the criteria of
`Q =(bml% dissolutionin 30 minutes. ThereIS no differencein dissolution performance as
`a result of the changes fi'om the current printed logo to a debossed logo
`
`"m2. Content
`
`(I!) (4)
`
`4. List of Excipients:
`Microcrystalline cellulose, colloidal anhydrous silica, lactose monohydrate, magnesium
`stearate,
`W"
`
`W" 400/
`W" (Hypromellose, Titanium Dioxide
`polyethylene glycol). Thus, all excipients listed (Colloidal anhydrous silica,
`hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose,
`polyethylene glycol, titanium dioxide) in the proposed labeling are acceptable.
`
`0’) (4)
`
`5. Process Selection (Unit Operations Summary)
`The manufacturing process
`mm.
`
`(b) (4)
`
`NDA-209089
`
`Executive SummaryS
`
`

`

`QUALITY ASSESSMENT
`
`6. Container Closure:
`
`Levocetirizine dihydrochloride Tablets, 5 mg is packaged in a white opaque 30 mL high
`density polyethylene (HDPE) bottle. The 30 mL bottle is proposed to contain 35, 45, 55
`and 80 counts of Levocetirizine dihydrochloride Tablets, 5 mg. The bottles are sealed
`with an aluminum foil induction inner seal and secured with a
`W"
`
`closure.
`
`W"
`"m" blister
`M“). aluminum foil lidding W"
`
`Levocetirizine dihydrochloride Tablets, 5 mg is also packaged in
`Blister Packs (Counts Not Provided).
`packs Will be sealed with
`0"" (peel push)
`“M" heat seal coating.
`7. Expiration Date & Storage Conditions
`Proposed expiration date of the drug product of 36 months is acceptable and supported by
`the real time stability data from the approved prescription product, in conjunction with
`the six months data from the proposed OTC product obtained at long-term storage
`conditions (25°C/60% RH) and 6-month study at accelerated conditions (40°C/75% RH).
`The storage statement will be written as “Store between 20° and 25°C (68°F and 77°F)”.
`This reflects the numerical value of the controlled room temperature [stored at 25°C
`(77°F) with excursions permitted to 15°C-30°C (59°F-86°F)], and is a modified version of
`the wording requested by the FDA, but aligns with the currently approved storage
`statement for the prescription levocetirizine hydrochloride.
`
`8. List of co—packaged components: None
`
`B. Summary of Drug Product Intended Use
`
`Proprietary Name of the Drug Product
`Noll Proprietary Name of the Drug Product
`
`X . ® A1131- 3 24 HR
`levocetirizine dih drochloride
`
`Non Proprietary Name of the Drug Substance
`
`levocetirizine dih drochloride
`
`ears.
`
`Proposed Indicafion(s) including Intended
`Piflent Popullflon
`
`For the temporary relief of runny nose,
`sneezing, itching of the nose or throat, and
`itchy, watery eyes due to hay fever or other
`upper respiratory allergies. Adults and
`children 12-64 years of age and Children 6-
`11 cars of a e.
`
`°“° “hm“ mg) m” “W's mg)
`a da for children 6-11 ears ofa_e'
`
`5m;2,5mforchi1dren6-ll
`
`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-209089
`
`Executive Summary6
`
`

`

`QUALITY ASSESSNIENT
`
`- Drug Product:
`
`2. Biowaivcrs/Biostudics-
`o Biowaiver Requests: Yes
`0 PK studies: N/A
`
`0 IVIVC: No
`
`D. Novel Approaches
`
`E. Any Special Product Quality Labeling Recommendations
`Established name of the drug product remains “levocetirizine dihydrochloride tablets” as
`approved in the prescription NDA 22-064, although based on Current FDA guidance
`(“Naming of drug products containing salt drug substances guidance for Industry”-June
`2015) and USP salt policy ofthe 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 “levocetirizine dihydrochloride tablets”.
`
`(m4)
`
`XyzaloAllergy 24HR
`(levocetlrizine dihydrochloride tablet)
`5 mg
`
`F. Life Cycle Knowledge Information (see table below)
`
`Risk Assessment:
`
`Factors that can
`attribute/CQ impact the CQA
`
`Probabi Severity Detectabilit FMECA Comment
`lity (0)
`of
`y (D)
`RPN
`Effect
`Number
`
`
`
`S
`
`2
`
`2
`
`2
`
`2
`
`- Formulation
`- Raw materials
`
`0 Process
`parameters
`- Scale/equipments
`- Site
`
`o Formulation
`0 Raw materials
`- Process
`
`parameters
`- Scale/equipment
`0 Site
`
`Physical
`stability (API)
`
`2
`
`2
`
`Assay method is
`deemed
`
`acceptable.
`Impurities are
`monitored.
`
`Stable based on
`data provided.
`
`NBA-209089
`
`Executive Summary7
`
`

`

`
`
`- Formulation
`
`- Raw materials
`
`0 Process
`
`parameters
`Gale/equipment
`
`Dissolution
`
`Similar release
`
`profile with the
`.
`
`- Site
`- Site
`
`0 Raw materials
`- Process
`
`parameters
`Scale/equipments
`
`- Exclude major
`reformulations
`
`- Alcohol dose
`
`dumpmg
`
`OVERALL ASSESSMENT AND SIGNATURES: EXECUTIVE
`
`SWARY
`
`
`
`NBA-209089
`
`Executive Summary8
`
`

`

`“WNW
`
`nut-alumna
`”mm.
`
`
`
`

`

`
`
`BIOPHARMACEUTICS
`
`Product Background:
`
`NDA: 209089
`
`Drug Product Name / Strength: Levocetirizine dihydrochloride tablet! 5 mg
`
`Route of Administration:0ral
`
`Applicant Name: UCB Inc.
`
`Review Summary:
`The Applicant submitted NDA 209089 for Xyzal® (levocetirizine dihydrochloride) tablets to
`propose prescription to over-the-counter (Rx-to-OTC) switch under 505(b)(2). It referenced to
`the prescription NDA 22-064 which was also submitted under section 505(b)(2) and was
`approved on 5/25/2007. The Applicant also plans to reference the safety and clinical efficacy of
`ZYRTEC® (cetirizine dihydrochloride) [5 mg and 10 mg tablets in NDA 19-835, oral syrup (5
`mg / ml) in NDA 20-346 and chewable tablets (5 mg and 10 mg) in NDA 21-621].
`
`The proposed nonprescription use for levoeetirizine dihydrochloride tablets is for the temporary
`relief of runny nose, sneezing, itching of the nose or throat, and itchy, watery eyes due to hay
`fever or other upper respiratory allergies.
`
`The proposed tablet formulation is the
`below:
`
`W" as shown
`
`Table 1: Quantitative Composition of Levocefirizine dihydrochloride Tablets, 5 mg
`Component
`Amount per tablet
`Function
`Reference to
`(mg)
`Standards
`
`Levocetmzune dlhydde‘llOHde
`
`5.00
`
`Actwe Ingredient
`
`Microcrystalhne cellulose
`
`COHOldal anhydrous Slllca
`
`Lactose monohydrate
`
`Magnesmm stearate
`
`03)“)
`(b) (4)
`
`00(4)
`
`in house
`specufncanon
`
`NF
`
`NF
`
`NF
`
`NF
`
`In house specmcalron
`
`USP
`
`0)) (4)
`
`

`

`QUALITY ASSESSMENT
`
`(b) (4)
`
`List Submissions being reviewed (table):
`
`Highlight Key Outstanding Issues from Last Cycle: None
`
`Concise Description Outstanding Issues Remaining: None
`
`BCS Designation
`
`Reviewer’s Assmment: Refer to prescription NDA 22-064
`
`Solubility: Refer to prescription NDA 22-064
`
`Permeability: Refer to prescription NDA 22-064
`
`Dissolution: Refer to prescription NDA 22-064
`
`Dissolution Method and Acceptance Criteria
`
`Reviewer’s Assessment:
`
`(mm
`
`The FDA approved dissolution method and acceptance criterion are shown below:
`
`

`

`QUALITY ASSESSMENT
`
`Apparatus:
`
`Medium:
`
`Speed:
`
`Sampling tlmc:
`
`Paddle.
`
`()(Mlml ofnutur
`
`SORI’M.
`
`IS. 30. 45min.
`
`Sumpling \ulumc:
`
`Sml
`
`Temperature:
`
`371) - -().5’('
`
`Acceptance Criterion: Q= 8% in 30 minutes.
`
`A dissolution comparison between printed tablets, debossed tablets, and split debossed tablets
`
`was performed using 12 tablets/batch of each tablet type according to the registered dissolution
`
`method UCB method moth-001455. The batch information for the dissolution testing is listed
`below in Table 2.
`
`Table 2: batch information for the dissolution testing
`Printed Tablet Debossed Tablet
`
`
`
`4
`on )
`
`Product code
`
`Batch Number
`
`Manufacturing Site
`
`Expiry
`
`The mean dissolution profile of the printed tablets, debossed tablets, and half debossed tablets
`
`are shown in Figure 1. This drug product is immediate release and the drug substance is highly
`
`soluble, hence the 12 value is not calculated. The mean dissolution profiles are similar among the
`whole mad tablets, whole debossed tablets, and half debossed tablets. With the specification
`of Q =
`3/0 in 30 minutes, all tablet formulations meet the acceptance criterion. Therefore, there
`
`is no difference in dissolution as a result of the changes from the current printed logo to a
`
`debossed logo.
`
`

`

`QUALITY ASSESSMENT
`
`Figure 1: Dissolution Profiles of Printed Tablets, Debossed, and Half Debossed Tablets
`12."
`
`135'
`
`
`
`amount[:73]
`
`#—
`
`[al.nuzgtu [our lll tun
`M‘mlr *rhl‘N-
`
`+ I'm.» lunv uhiuzn
`
`[=_lJUL-‘:L;f hurl IL'JJII,
`hil' ’nhlrrr
`
`LI
`
`L-
`
`in
`
`-'J
`
`H
`
`'uI
`
`timc[min]
`
`{Assess method development, method robustness, and criteria; modeling approach}
`
`Clinical relevance ofdissolution method & acceptance criteria (eg., IVIVR, IVIVC, In Silico
`
`Modeling, small scale in viva)
`
`Reviewer’s Assessment: n/a
`
`Application ofdissolution/[WC in QbD
`
`Reviewer’s Assessment: nla
`
`MODIFIED RELEASE ORAL DRUG PRODUCTS —In-Vitro Alcohol Dose Dumping
`
`Reviewer’s Assessment: n/a
`
`In- Vitro Release Testing (II/R1) for Semi-Solid Products
`
`Reviewer’s Assessment: n/a
`
`

`

`
`
`In- Vitro Penneation Testing (II/PI) for fiansdermal/Topical Products
`
`Reviewer-’5 Assessment: n/a
`
`In- Vitro Dissolution Testingfor Abuse-deterrent Products
`
`Reviewer’s Assessment: n/a
`
`In- Vitro BE Evaluation for Pulmonary Products
`
`Reviewer’s Assessment: n/a
`
`EXTENDED RELEASE DOSAGE FORMS' —Extended Release Claim
`
`Reviewer’s Assessment: nla
`
`Bridging ofFormulations
`
`Reviewer’I AIsesIment: n/a
`
`Biowaiver Request
`
`Reviewer’s Assessment:
`
`The Applicant reported that other than the difl‘erence in the physical appearance ofthe tablet,
`
`there are no other changes from the prescription levocetirizine tablet product to the
`
`nonprescription levocetirizine tablet product. The applicant submitted a biowaiver request with
`
`supporting dissolution data (printed vs. debossed vs. halfdebossed tablets) based on the fact that
`
`the same drug substance, manufacturing process and test methods, and
`are utilized.
`
`W" sites
`
`R
`
`Regional Information
`
`Comparability Protocols
`
`

`

`QUALITY ASSESSMENT
`
`Reviewer’s Assessment: n/a
`
`Post-Approval Commitments
`
`Reviewer’s Assessment: nla
`
`Lifecycle Management Considerations
`
`Reviewer’s Assessment: n/a
`
`List ofDeficiencies: None.
`
`Primaly Biopharmaceutics Reviewer Name and Date:
`
`An-chi (Angela) lu, Pharm D. 8/1/2016
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`I concur.
`
`1 1/29/16
`
`Tien-Mien Chen, Ph.D.
`
`Acting Biopharm Lead
`
`DB/ONDP/OPQ
`
`

`

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`
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`cum: mmrasdmmuoomm
`
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`Dull: 1mm comm
`cum: mrmm1ms1m
`
`18 Page(s) has been Withheld in Full as b4 (CCIITS) immediately following this page
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`£51m.”
`.49
`"
`‘3’!
`:
`
`5
`
`have...
`
`DATE:
`
`23 August 2016
`
`TO:
`
`NDA 209-090
`
`FROM:
`
`Denise Miller
`
`CDER/OPQ/OPF/DMA/Branch II, Microbiologist
`
`THROUGH: Neal J. Sweeney Ph.D.
`CDER/OPQ/OPF/DMA/Branch 11, Senior Microbiologist
`
`SUBJECT:
`
`Division of Microbiology Review
`Product: Xyzal Allergy 24 HR
`Sponsor: UCB Inc.
`
`This product is a currently marketed FDA approved product. It is a non-sterile oral solution.
`
`NDA 209-090 is for this same product to be marketed as an over-the-counter (OTC) product.
`There are no proposed changes to the formulation, manufacturing of the product, or the release
`specifications, and as such there are no quality microbiology concerns for the subject NDA and
`further review of the NDA is not required.
`
`The recommendation is for approval from the Product Quality Microbiology review standpoint.
`
`[END]
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209090
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`Application #: 209090
`
`Submission Type: Standard
`
`Establisheleroper Name:
`Levocetirizine dihydrochloridel
`Xyzal® Allergy 24 HR
`
`Appllcant: UCB Inc.
`
`Latter Date: March 31, 2016
`
`Dosage Form: Oral solutlon
`
`Chemleal Type: Type 8
`— Partial Rx to OTC
`Switch
`
`Stamp Date: March 31, 2016
`
`Strength: 2.5 mgIS mL (0.5
`mg/mL)
`
`FILING CONCLUSION
`-—-m—mm—
`DOES THE OFFICE OF
`PHARMACEUTICAL
`
`QUALITY RECONIMEND
`THE APPLICATION TO BE
`FILED?
`
`filjn- comments stated above?
`
`If the application is not fileable
`from the product quality
`perspective, state the reasons and
`provide filing comments to be
`sent to the A Jolicant.
`Are there any potential review
`issues to be forwarded to the
`
`Applicant, not including any
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209090
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`B.
`
`NOTEWORTHY ELEMENTS OF THE
`APPLICATION
`
`New Molecular Emi
`Botanical
`Naturall derived Product
`
`'11E»a :1
`
`1
`
`
`
`Narrow Theta-cutie Index |
`PET Dru_
`“——
`-_—I!I
`_I!I
`_m >3
`mn_llllzc
`“I”_I!I v14
`II._IH
`3.
`Solid dispersion product
`Oral disintey : n. -_ tablet
`Modified release . oduct
`
`VA
`
`LniiiiiilEEEEEEE
`
`y—n 7.
`
`Liposome product
`Biosimih'ar . duct
`Combination Product
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209090
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`'
`
`-—:
`
`x ato Considerations
`I >3IIl
`D
`
`.
`1.
`.
`
`USAN Name Assi- H
`End of Phase II/Pre-NDA A y cements
`SPOTS
`
`S . cial Products On-line Trackin; S stem
`Citizen Petition and/or Controlled Correspondence
`Linked to the A- -lication
`L1
`.
`Comparability Protocol(s)
`25
`.
`Other: Pre-NDA meetin_
`PIND 126506 mee' . ; on 10/01/2015
`El
`fl0E
`
`Denna
`
`OaE:3
`
`Dru Substance 0vera_-
`
`Formulation
`Process
`Anal
`-'cal Methods
`3
`
`Design Space
`
`E!
`
`E!
`
`Real Time Release Testin ’ TRT
`Parametric Release in lieu of Sterili Te '- 1
`Alternative Microbiolo ‘cal Test Methods
`Process Anal
`I'cal Technolo a
`
`Non-compendial Analytical
`Procedures and/or
`
`:1IE-%H I II I|
`
`Microbial
`
`
`
`B.
`E.
`5
`.
`III
`specifications
`,
`. U' - ue anal u'cal methodolo;
`Exci . ients of Human or Animal Ori
`E“
`Novel Exci ients
`m
`Nanomaterials
`I lIIl
`
`EI
`Hold Times Exceeding 30 Days
`Genotoxic u uurities or Structural Alerts
`IIIIII
`an»:
`
`'
`
`43
`
`.
`
`I!-
`
`Continuous Manufacturin
`
`B Otheruniquemanufacturingprocess
`
`Use of Models for Release (IVlVC, dissolution
`models for real time release .
`
`I
`L-
`— stem or dosae form
`New deliv
`
`I‘- DEDE
`Novel BE study designs
`New . oduct desig-
`
`49.
`
`Contact Office of Testing and Research for review team considerations
`2Contact Post Marketing Assessment stafl‘ for review team considerations
`
`-
`
`
`c.
`
`FILING cousnoERAnons
`
`1.12.14 and cateon'cal exclusion for
`
`Has an environmental assessment report or
`categorical exclusion been provided?
`
`Justification for no extraordinary
`circumstances has been provided (section
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209090
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`FILING CONSIDERATIONS
`
`levocetirizine dihydrochloride oral
`solution, 2.5 mg/5 mL is claimed
`according to 21 CFR 25.31(b) and 25.31
`
`No comparability protocolis proposed.
`Not manufactured with materials of
`animal or human origin.
`
`Quality Overall Summary section is not
`included and the sponsor will submit this
`information in June, 2016.
`
`Is the Quality Overall Summary (QOS) organized
`adequately and legible? Is there sufficient
`informationin the following sections to conduct a
`
`'
`
`Facilities and Equipment
`Adventitious Agents Safety
`Evaluation
`
`Novel Excipients
`El Regional Information
`0
`Executed Batch Records
`
`0 Method Validation Package
`0 Comparability Protocols
`
`FACILITY INFORMATION
`
`5/12/16). Is a statement provided that all facilities are ready
`
`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 nawrally-
`derived API only, are the facilities responsible for
`critical intermediate or crude API manufacturing, or
`performing upstream steps, specified in the
`application? Ifnot, has ajustification been
`provided for this omission? For each site, does the
`application list:
`Name of facility,
`Full address of facility including street, city,
`state, country
`FEI number for facility (ifpreviously registered
`with FDA)
`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
`
`for GM? inspection at the time of submission?
`For BLA:
`
`CI
`El
`
`Is a manufacturing schedule provided?
`Is the schedule feasible to conduct an
`-:- ctionwithinthereviewc cle?
`
`’2
`
`I
`
`Cross —reference to the approved NDA
`22-064 (Xyzal tablets, 5 mg (approved
`May 25, 2007). Approved suppliers of
`drug substance are UCB
`Farchim S.A. Bulle, Switzerland;
`
`(”(4)
`(mu)
`
`Address and contact information ofthe
`drug substance facilities are included
`(”I“) following an IR (dated
`
`'2
`
`I
`
`I
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209090
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`FILING CONSIDERATIONS
`
`For DMF review, are DMF # identified and
`authorization letter(s), included US Agent Letter of
`Authorization provided?
`
`
`E
`
`Refers to NDA 22-064
`
`Refers to NDA 22-064.
`
`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
`El manufacture
`
`0
`
`Includes production data on drug submance
`manufactured in the facility intended to be
`licensed (including pilot facilities) using
`the final production process(es)
`Includes descriptions of changes in the
`manufacturing process from material used
`in clinical to commercial production lots —
`BLA only
`Includes complete description of product
`lots and their uses during development —
`BLA only
`characterization of drug substance
`control of drug substance
`0
`Includes data to demonstrate comparability
`ofproduct to be marketed to that used in
`the clinical trials (when significant changes
`in manufacturing processes or facilities
`have occurred)
`Includes data to demonstrate process
`consistency (i.e. data on process validafion
`lots) — BLA only
`reference standards or materials
`
`container closure system
`stability
`0
`Includes data establishing stability of the
`
`product through the proposed dating period
`
`and a stability protocol describing the test
`methods used and time intervals for
`
`product assessment
`
`
`
`DRUG PRODUCT INFORMATION
`
`Is the Drug Product section [3.2.P] organized
`adequately and legible? Is there sufficient
`information in the following sections to conduct a
`review?
`
`#2
`
`I
`
`I
`
`Refers to NDA 22-157.
`
`Description and composition of the drug
`-
`~ auct is included.
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209090
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`0.
`
`FILING CONSIDERATIONS
`
`Pharmaceutical development includes
`description of the changes fi’om the
`approved product (NDA 22-064)
`
`
`
`El
`
`El Description and Composition of the Drug
`Product
`Pharmaceutical Development
`0
`Includes descriptions of changes in the
`manufacturing process from material used
`in clinical to commercial production lots
`Includes complete description of product
`lots and their uses during development
`Manufacture
`
`0
`
`o
`
`Ifsterile, are sterilization validation studies
`submitted? For aseptic processes, are
`bacterial challenge studies submitted to
`support the proposed filter’l
`Control of Excipients
`Control of Drug Product
`0
`Includes production data on drug product
`manufactured in the facility intended to be
`licensed (including pilot facilities) using
`the final production process(es)
`Includes data to demonstrate process
`consistency (i.e. data on process validation
`lots)
`Includes data to demonstrate comparability
`ofproduct to be marketed to that used in
`the clinical trials (when significant changes
`in manufacturing processes or facilities
`have occurred)
`0 Analytical validation package for release
`test procedures, including dissolution
`Reference Standards or Materials
`
`Container Closure System
`0
`Include data outlined in container closure
`
`guidance document
`Stability
`0
`Includes data establishing stability of the
`product through the proposed dating period
`and a stability protocol describing the test
`methods used and time intervals for
`
`product assessment
`APPENDICES
`REGIONAL INFORMATION
`
`BIOPHARMACEUTICS
`
`

`

`I I
`i
`-m-_utential? -
`
`Are there adequate in vitro and/or in vivo data
`supporting the bridging of formulations throughout
`the drug product’s development and/or
`manufacturing changes to the clinical product?
`(Note whether the to-be-marhetedproduct is the
`
`same product used in the pivotal clinical studies)
`Does the application include a biowaiver request?
`If yes, are supportive data provided as per the type
`of waiver requested under the CFR to support the
`requested waiver? Note the CPR section cited.
`
`U
`
`E
`
`E]
`
`IZI
`
`El
`
`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NDA-209090
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`FILING CONSIDERATIONS
`
`If the Biopharmaceutics team is responsible for
`reviewing the in vivo BA or BE studies:
`0 Does the application contain the complete BA/BE
`data?
`0 Are the PK files in the correct format?
`
`0 Is an inspection request needed for the BE
`study(ies) and complete clinical site information
`provided?
`
`IX]
` For a modified release dosage form, does the
`
`alcoholdose-d
`
`application include information/data on the in-vitro
`
`For an extended release dosage form, is there
`enough information to assess the extended release
`des'_- : ion claim as erthe CFR?
`
`I
`
`I
`
`>14
`
`Is there a claim or request for BCS I designation? If I
`yes, is there sufficient permeability, solubility,
`stabilit
`and dissolution data?
`REGIONAL INFORMATION AND APPENDICES
`
`it
`
`I
`
`I
`
`'14
`
`I
`
`I
`
`I
`
`it
`
`Refers to NDA 22-064 & 22-157.
`
`Are any study reports or published articles in a
`foreign language? If yes, has the translated version
`been included in the submission for review?
`
`Are Executed Batch Records for drug substance (if
`: U' licable and dru_ . duct available?
`Are the following information available in the
`Appendices for Biotech Products [3 .2.A]?
`El
`ficilities and equipment
`manufacturing flow; adjacent areas
`other products in facility
`equipment dedication, preparation,
`sterilization and storage
`procedures and design features to prevent
`contamination and cross-contamination
`
`adventitious agents safety evaluation (viral and
`non-viral) e.g.:
`o
`avoidance and control procedures
`0
`cell line ualification
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209090
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`FILING CONSIDERATIONS
`
`0
`0
`0
`
`other materials of biological origin
`viral testing of unprocessed bulk
`viral clearance studies
`
`testing at appropriate stages ofproduction
`0
`novel exci . ients
`
`El
`
`Products:
`
`El Compliance to 21 CFR 610.9: Ifnot using a
`test method or process specified by regulation,
`data are provided to show the alternate is
`equivalent to that specified by regulation. For
`example:
`
`LAL instead ofrabbit pyrogen
`0
`o Mycoplasma
`Compliance to 21 CFR 601.2(a): Identification by
`lot number and submission upon request, of
`sample(s) representative of the product to be
`marketed with summaries of test results for those
`
`samples
`
`Risk Assessment:
`
`attribute/CQA impact the CQA
`
`Factors that can
`
`
` Are the following information available for Biotech
`- Scale/equipment
`
`Product
`
`'
`
`De)tectaability
`
`Number
`
`Assay, stability
`
`- Formulation
`- Raw materials
`
`Refers to approved
`NDA 22157.
`
`- Process parameters
`' Scale/equipments
`- Site
`
`- Formulation
`- Raw materials
`- Process parameters
`
`- Formulation
`
`Container closure
`
`Refers to approved
`NDA 22157.
`
`Meets USP<698> .
`
`

`

`
`
`
`OFFICE OF PHARMACEUTICAL QUALITY
`FILING REVIEW NBA-209090
`
`
`
`
`
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`
`
`
`
`
`
`- Site
`
`
`
`- Formulation
`
`
`
`
`
`- Raw materials
`
`
`- Process parameters
`
`
`- Scale/equipment
`
`
`
`
`
`3
`
`
`
`3
`
`
`
`2
`
`
`18
`
`
`
`Meets USP<61>.
`
`
`
`
`
`
`
`
`SWa pa n K De —S ou=People, cn=Swapan K. De-S,
`
`'
`
`
`
`
`
`
`
`Digitally signed by Swapan K. De -5
`
`
`
`
`DN: c=US, o=U.S. Government, ou=HHS, ou=FDA,
`
`
`
`
`
`0.9.2342.19200300100.1.1=1300132497
`
`Date: 2016.05.26 1 1:26:32 -04‘00'
`
`
`
`
`
`
`
`
`
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209089
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`Application #: 209089
`
`Submission Type: Standard
`
`EstablishedIProper Name:
`Levocetirizine dihydrochloridel
`Xyzal® Allergy 24 HR
`
`Appllcant: UCB Inc.
`
`Letter Date: March 31, 2016
`
`Dosage Form: Tablet
`
`Chemlcal Type: Type 8
`_ Rx to OTC Switch
`
`Stamp Date: March 31, 2016
`
`Strength: 5 mg
`
`FILING CONCLUSION
`
`-—-mm—
`DOES THE OFFICE OF
`PHARMACEUTICAL
`
`filin- comments stated above?
`
`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 A J-licant.
`Are there any potential review
`issues to be forwarded to the
`
`Applicant, not including any
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209089
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`B.
`
`NOTEWORTHY ELEMENTS OF THE
`APPLICATION
`
`-<I!
`
`New Molecular Emi
`Botanical
`Naturall derived Product
`
`'1E»9. 2.
`
`1
`
`VA
`
`
`
`Narrow Theta-cutie Index |
`PET Dru_
`“——
`-_—I!I
`_I!I
`_m >3
`mn_llllvzc
`“I"_I!I v14
`II-_Ifl
`3.
`Solid dispersion product
`Oral disintey : n. -_ tablet
`Modified release . oduct
`
`LniiiiiilEEEEEEE
`
`y—n 7.
`
`Liposome product
`Biosimiliar . duct
`Combination Product
`
`

`

`OFFICE OF PHARMACEUTICAL QUALITY
`
`FILING REVIEW NBA-209089
`
`DIVISION OF NONPRESCRIPTION DRUG PRODUCTS
`
`'
`
`-—:
`
`x ato Considerations
`I >3IIl
`D
`
`.
`1.
`.
`
`USAN Name Assi- H
`End of Phase D/Pre-NDA A y cements
`SPOTS
`
`S . cial Products On-line Trackin; S stem
`Citizen Petition and/or Controlled Correspondence
`Linked to the A- -lication
`L1
`.
`Comparability Protocol(s)
`25
`.
`Other: Pre-NDA meetin_
`PIND 126506 mee' . ; on 10/01/2015
`El
`fl0E
`
`Denna
`
`OaE:3
`
`Dru Substance Overa_-
`
`Formulation
`Process
`Anal
`-'cal Methods
`3
`
`Design Space
`
`Real Time Release Testin_ ’ TR
`Parametric Release in lieu of Sterili Te '- 1
`Alternative Microbiolo ‘cal Test Methods
`
`I'cal Technolo 3
`Process Anal
`Non-compendial Analytical
`Procedures and/or
`
`:1IE-%H I II I|
`
`Microbial
`
`'
`
`E!
`
`E!
`
`43
`
`.
`
`
`
`B.
`E.
`5
`.
`III
`specifications
`,
`. U' - ue anal u'cal methodolo;
`Exci . ients of Human or Animal Ori
`E“
`Novel Exci ients
`m
`Nanomaterials
`I lIIl
`
`EI
`Hold Times Exceeding 30 Days
`Genotoxic u uurities or Structural Alerts
`IIIIIl
`an»:
`
`Continuous Manufacturin
`I!-
`
`
`B Otheruniquemanufacturingprocess
`
`Use of Models for Release (IVlVC, dissolution
`models for real time release .
`
`I
`L-
`— stem or dosae form
`New deliv
`
`I‘- DEDE
`Novel BE study designs
`New . oduct desig-
`
`49.
`
`Contact Office of Testing and Research for review team considerations
`2Contact Post Marketing Assessment st