CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
` APPLICATION NUMBER:
`
`
`
` 212640Orig1s000
`
` PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`

`

`
`
` RECOMMENDATION: Approval
`
`
`
` NDA 212640
`
`
`
` Review 1
`
`
`
`
`
` Drug Product Name
`
`Exservan™ (riluzole)
`
`
`
`
`
` Dosage Form
`
`
`
` Strength
`
`
`
` Oral film
`
`
`
` 50 mg
`
`
`
` Route of Administration Oral
`
`
`
`
`
` Rx/OTC Dispensed
`
`
`
` Rx
`
`
`
` Applicant
`
`
`
` Aquestive Therapeutics
`
`
`
`
`
` US agent, if applicable
`
`
`
`QUALITY TEAM
`
`
`
`
`
` Discipline
`
`
`
` Primary Assessment
`
`
`
` Secondary Assessment
`
`
`
` Drug Substance
`
`
`
` Gaetan Ladouceur
`
`
`
` Suong (Su) Tran
`
`
`
` Drug Product/Labeling
`
`
`
` Mariappan Chelliah
`
`
`
` Wendy Wilson-Lee
`
`
`
` Manufacturing
`
`
`
` Microbiology
`
`
`
` Tianhong Tim Zhou
`
`
`
`
`
` Nallaperumal Chidambaram
`
`
`
` N/A
`
`
`
` N/A
`
`
`
` Biopharmaceutics
`
`
`
` Kaushalkumar Dave
`
`
`
` Ta-Chen Wu
`
`Regulatory Business
`
` Process Manager
`
`
`
` Dahlia Walters
`
`
`
` Application Technical Lead
`
`
`
` Martha Heimann
`
`
`
` Laboratory (OTR)
`
`
`
` Environmental
`
`
`
` N/A
`
`
`
` N/A
`
`
`
` N/A
`
`
`
` N/A
`
`
`
`
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`

`

`
`
` Submission(s) Reviewed
`
`
`
`
`
` Document Date
`
`
`
` Discipline(s) Affected
`
`
`
` SD-001, Original NDA
`
`SD-003, Response to 74-Day
`
` Letter comments
`
`
`
` 1/31/2019
`
`
`
` 5/13/2019
`
`
`
` All
`
`
`
` All
`
`
`
` SD-005, Response to IR
`
`
`
` 7/26/2019
`
`
`
` Manufacturing
`
`
`
` SD-006, Labeling/Container
`
`
`
` 8/28/2019
`
`
`
` Labeling
`
`
`
` SD-007, Response to IR
`
`
`
` 9/5/2019
`
`Drug Product,
` Biopharmaceutics
`
`
`
`
`
` SD-008/Labeling/Container
`
`
`
` 9/25/2019
`
`
`
` Labeling
`
`
`
` SD-009, Response to IR
`
`
`
` 10/1/2019
`
`
`
` Biopharmaceutics
`
`
`
` SD-009, Response to IR
`
`
`
` 10/1/2019
`
`
`
` Biopharmaceutics
`
`
`
`
`
`
`
`
`
` NDA 212640
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 2
`
`
`
`
`
` 10/16/2019
`
`

`

`QUALITY ASSESSMENT DATA SHEET
`
`
`
`
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`
`
`
`
` A. DMFs:
`
`
`
`
`
`
` DMF # Type
`
`
`
`
`
` II
`
`
`
` IV
`
`
`
` III
`
`
`
` IV
`
`
`
` IV
`
`
`
` Holder
`
`
`
` Item Referenced Status
`
`
`
`Date
`
`Assessed
`
`
`Adequate
`
`
`
` 3/6//2019
`
`
`
` Comments
`
`
` Reviewed by G.
`
` Ladouceur
`
`Adequate 1
`
`
`
`
`
` N/A 2
`
`
`
` N/A 2
`
`
`
` N/A 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1 No updates to DMF since previous adequate review dated 9/22/2017.
`
`
`
` 2 Adequate information provided in NDA.
`
`
` B. Other Documents: IND, RLD, or sister applications
`
`
`
`
`
`
`
` Document
`
`
`
` Application Number
`
`
`
` Description
`
`
`
` NDA
`
`
`
` 20599
`
`
`
` IND
`
`
`
` NDA
`
`
`
` 130939
`
`
`
` 209080
`
`Rilutek® (riluzole) tablets, Covis Pharma NDA
`referenced under 505(b)(2) to support safety and
`
` efficacy of riluzole.
`
`
`
` Aquestive Therapeutics, development of riluzole oral film
`
`
`
` Italfarmaco S.p.A. NDA for Tiglutik™ (riluzole) oral
`
` suspension (competitor product). Approved 9/5/2018.
`
`
`
`
` 2. CONSULTS
`
`
`
`
`
`
`
` None
`
`
`
`
`
` NDA 212640
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 3
`
`
`
`
`
` 10/16/2019
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`EXECUTIVE SUMMARY
`
`
`
`
`
`
`
` I. RECOMMENDATIONS AND CONCLUSION ON APPROVABILITY
`
`
`
` The OPQ review team recommends Approval of NDA 212640 for Exservan™
`
`
`
`
`
`(riluzole) oral film. The application, as amended in response to Agency information
`
`
` requests (IRs), provides adequate information to ensure that the applicant can
` consistently manufacture a product that is suitable for use by the intended patients.
`
`
`
`
` II. SUMMARY OF QUALITY ASSESSMENTS
`
`
`
`
`
` A. Product Overview
`
`
`
` Aquestive Therapeutics developed Exservan (riluzole) oral film 50 mg as an
`
`
`
`
`
` alternative to Rilutek (riluzole) tablets for treatment of amyotrophic lateral sclerosis
` (ALS) in patients who have difficulty swallowing tablets.1 The applicant requests
`
`
`
` approval of the product under a 505(b)(2) NDA that relies on the prior approval of
`
`
`
` Rilutek (NDA 20599). FDA granted Orphan designation for this product.
`
`
`
` Riluzole oral film is designed to disintegrate rapidly when placed on the tongue and
`release the active ingredient as a solid suspended in saliva. Gastrointestinal
`absorption occurs through natural salivary drainage and intentional swallowing of
`
` saliva, followed by dissolution of riluzole in the stomach. The applicant identified
`
`ubjective S
`
`A ttributes, not critical
`
`as
`
`
`
` to quality or performance, but desirable for the finished drug product. Identity,
`
` appearance, assay, content uniformity, degradation, microbiological limits,
`
`
`, dissolution, and disintegration
`
`elemental impurities,
`
` are identified as Quality Attributes that ensure performance of the drug product. The
`
`
` initial risk assessment identified palatability as a moderate risk attribute for the
`
` product.
`
`
`
`
`
` Proposed indication(s) including
` intended patient population
`
`
`
`
`
`
` Treatment of patients with amyotrophic lateral
`
`
` sclerosis (ALS).
`
`
`
` Duration of treatment
`
`
`
`
`
`
`
` Chronic
`
`
`
` 100 mg
`
`
`
` None
`
`
`
` Maximum daily dose
`
`
`
`
`
`
` Alternative methods of
` administration
`
`
`
`
`
`
`
`
`
`
`
`
` 1 Prior to the September 5, 2018 approval of Tiglutik™ (riluzole) oral suspension (NDA 209080,
`
`
` Italfarmaco S.p.A.), the only approved dosage form for riluzole was a conventional tablet.
`
`
`
`
` NDA 212640
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 4
`
`
`
`
`
` 10/16/2019
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` B. Quality Assessment Overview
`
`
`
`
`
` Drug Substance:
`
`
`
` Adequate
`
`
` Riluzole is a well-characterized small molecule that is manufactured for the applicant
`
` Information regarding manufacture and control
`
`
`by
`
` of the bulk drug substance is incorporated by cross-reference to the manufacturer’s
` The DMF was reviewed and is deemed adequate to support approval
`
`DMF
`
`
` of the NDA. Summary information submitted directly to the NDA, including general
` properties and the drug substance specification, is consistent with the information in
`
`
`
` the DMF and Riluzole USP monograph requirements.
`
`
`
`
`
`
`
` Drug Product:
`
`
`
`
`
` Adequate
`
`The proposed product is a polymer-based film matrix that contains 50 mg of riluzole
`
`
` per film. The formulation is similar to previous products developed by the applicant
` (e.g., Zuplenz® and Suboxone®); however, the riluzole oral film formulation
`
`incorporates polacrilex resin and flavors
`
`
` . The applicant evaluated the adequacy of the formulation’s ability to
` mask riluzole’s organoleptic effects in a pilot BA/BE study (Study No. 1897). There
`
`
` are no novel excipients and maximum daily exposures for excipients are within
`
` levels for FDA-approved products.
`
`
` The proposed specification is adequate to assure the identity, strength, quality,
`
` purity, and potency, and bioavailability of the drug product and batch-to-batch
` consistency through the product’s lifecycle. The applicant has validated all non­
`
`compendial analytical methods used for testing the drug product. Acceptance
`criteria for impurities are consistent with ICH Q3B(R2) guidance and the USP
`
` monograph for riluzole tablets. The batch data provided for three registration
` batches demonstrate that the Applicant can manufacture the drug product with
`
`
` consistent quality.
`
`Each riluzole oral film will be packaged in an aluminum foil pouch. The secondary
`container is a cardboard carton that contains 60 individually pouched riluzole oral
`
`
` films. The container closure system is adequate to maintain the product quality
`through the proposed shelf-life as demonstrated by the stability data. Up to
`
` 24 months of long-term stability data available for the three primary batches
` demonstrate the drug product is stable and no trending was noted for any of the
`
` quality attributes. The proposed shelf-life of 24 months, when stored at
` controlled room temperature: 20°–25° (68°–77° F) is granted.
`
`
`
`
`
`
`
` Manufacturing:
`
`
`
`
`
` Adequate
`
`
`
` The proposed commercial manufacturing process for Exservan is divided by the
`
`applicant into
`
`
`
`
`
` NDA 212640
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 5
`
`
`
`
`
` 10/16/2019
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` Critical process parameters for the proposed manufacturing process were
`
` kg batch scale and applied to five
`
`
` optimized at
`
`
` kg engineering batches
`
` (commercial scale).
`
`
`
` All facilities involved in the manufacture and testing of Riluzole USP and Exservan
`
`
` (riluzole) oral film are currently acceptable.
`
`
`
`
`
` Biopharmaceutics:
`
`
`
` Adequate
`
`
`
`
`
` The proposed dissolution method for the proposed Riluzole Oral Film, 50 mg, is as
` follows: 900 mL of 0.1N HCl using USP Apparatus 1 (basket) at 50 rpm. The
`
`
` provided dissolution data demonstrate that the proposed dissolution method can
`
` discriminate between the target product and a deviant batch prepared with
`
`
` content. However, the proposed method could not discriminate between the target
`
`and other deviant batches prepared with altered composition and process
`
`
`
` parameters. As the proposed product is designed to disintegrate very rapidly and
`the drug substance has high solubility in the proposed dissolution medium,
`
`
`
`
` development of a discriminating dissolution method is considered challenging. The
` applicant selected appropriate dissolution testing conditions for the product, and the
`
`
`
` provided data demonstrate some discriminating ability. Thus, the proposed
`
`
`
`dissolution method is deemed adequate for quality control testing of the proposed
`
`
`
`
` product. Based on the dissolution profile data from the clinical and registration
`
` batches and the data from discriminating ability studies, the proposed dissolution
`
`
`method is likely to be more discriminating, and thus be able to identify potential
`
` quality issues, if sampling is performed at an earlier time-point. Thus, it was
` recommended that the applicant revise the originally proposed dissolution
`
`
`
`acceptance criterion of ‘
`
` % (Q) at 20 minutes.’
`’ to ‘NLT
`The applicant agreed to the recommendation and revised the dissolution acceptance
`
`
` criterion accordingly. The revised dissolution acceptance criterion is deemed
` adequate for quality control testing of the proposed product.
`
`
`
`
`
`
`
`
`
` Labeling:
`
`
`
`
`
` Adequate
`
`
`
` The proposed labeling is deemed adequate from a quality perspective
`
`
`
`
`
` Environmental:
`
`
`
` Adequate
`
`The applicant submitted a claim for categorical exclusion under 21 CFR §25.31(a).
`Riluzole oral film is intended as an alternative to Rilutek tablets for the same
`indication (ALS), in the same patient population, and with the same dosing regimen.
`
` Approval of the application would not increase use of riluzole. The claim for
`
` categorical exclusion is granted.
`
`
`
`
`
` Methods Verification:
`
`
`
`Verification of analytical procedures submitted in the NDA by FDA laboratories was
`
` not requested during the review.
`
`
`
` NDA 212640
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 6
`
`
`
`
`
` 10/16/2019
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`
`
`
`
` C. Risk Assessment
`
`
`
` From Initial Risk Identification
`
`
`
` Review Assessment
`
`
`
`
`
` Attribute/CQA
`
`
` Factors that can impact
` the CQA
`
`
`
`Initial Risk
`
` Ranking
`
`
`
` Risk Mitigation Approach
`
`
` Final Risk
`
` Evaluation
`
`
`
` Comments
`
`
`
` Assay, stability
`
` Formulation, container
`
`closure,
`, process
` parameters
`
`
`
`
` Content uniformity
`
` (CU)
`
` Formulation, raw materials,
`
`
` process parameters,
` scale/equipment/site
`
`
`
` Physical stability
`
` (solid state)
`
` Formulation, raw materials,
`
`
` process parameters,
` scale/equipment/site
`
`
`
`
` Microbial limits
`
`
`
` Dissolution
`
`
`
` Formulation, raw materials,
`
` process parameters,
`
` container closure
`
`
`
` Formulation, raw materials,
`
`
` process parameters,
` scale/equipment/site
`
`
`
`
` Palatability
`
`
` Formulation, raw materials,
`
` container closure
`
`
`
`
` NDA 212640
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` L
`
`
`
` L
`
`
`
` L
`
`
`
` L
`
`
`
` L
`
`
`
` M
`
`
`
` Adequate
`
`
`
`
`
` Adequate
`
`
`
`
`
`
`
` Adequate
`
`
`
` Adequate
`
`
`
` Adequate
`
`
`
` Adequate
`
`
`
`
`
`
`
`
`
`
`
` Page 7
`
`
`
`
`
` 10/16/2019
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` From Initial Risk Identification
`
`
`
` Review Assessment
`
`
`
`
`
` Attribute/CQA
`
`
` Factors that can impact
` the CQA
`
`
`
`Initial Risk
`
` Ranking
`
`
`
` Risk Mitigation Approach
`
`
` Final Risk
`
` Evaluation
`
`
`
` Comments
`
`
`
` Disintegration
`
` Formulation, raw materials,
`
`
` process parameters,
` scale/equipment/site
`
`
`
`
` Film Integrity
`
` Formulation, container
`
`closure, raw materials,
`process parameters,
`scale/equipment/site,
`
`
`
`
` Particle Size
`
`
`
` Raw material particle size
`
`
`
` L
`
`
`
` L
`
`
`
` L
`
`
`
` Film Adhesion
`
`
`
` Formulation, raw materials,
`process parameters,
`
` scale/equipment/site
`
`
`
` L
`
`
`
` N/A
`
`
`
` Adequate
`
`
`
`
`
`
`
`
`
` Adequate
`
`Particle size does not impact on
`
` dissolution profile.
`
`
`
`Film only needs to adhere to
` tongue for brief period while it
`
`Not a
`disintegrates
`
` CQA
`
`
`
` Film dimensions
`
`Process parameters,
`
` scale/equipment/site
`
`
`
` L
`
`
`
` Adequate
`
`
`
`
`
` NDA 212640
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 8
`
`
`
`
`
` 10/16/2019
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
` D. List of Deficiencies for Complete Response: Not applicable.
`
`
`
`
`
`
`
` Application Technical Lead Name and Date: Martha R. Heimann 10/16/2019.
`
`
`
`
`
`
`
`
`
` NDA 212640
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 9
`
`
`
`
`
` 10/16/2019
`
`

`

`Martha
`Heimann
`
`Digitally signed by Martha Heimann
`Date: 10/16/2019 05:39:12PM
`GUID: 504f845f00000ed260627d268a8cdc9d
`
`
`
`Reference ID: 4506982
`Reference ID: 4525554
`
`
`28 Page(s) have been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`

`

`
`
`
`
` CHAPTER IV: LABELING
`
`
` IQA NDA Assessment Guide Reference
`
`
`
` 1.0 PRESCRIBING INFORMATION
`
` Assessment of Product Quality Related Aspects of the Prescribing
`Information:
`
`
`
`
`
`
`
` 1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION
`
` Information Provided
`
` in the NDA
`
`
`
` Assessor’s Comments
`
`
`
`
`
` Item
`
`
` Product Title in Highlights
` Proprietary name
`
`
` Exservan
`
`Established name(s)
` riluzole
`
` Route(s) of administration
`
`
` Oral
`
` Dosage Forms and Strengths Heading in Highlights
`
`
`Summary of the dosage
` 50 mg
`
`form(s) and strength(s)
`
` in metric system.
`Assess if the tablet is
`scored. If product meets
` guidelines and criteria for a
`
`scored tablet, state
` “functionally scored”
`
`For injectable drug
`products for parental
`administration, use
`
` appropriate package type
` term (e.g., single-dose,
`
`multiple-dose, single­
`
` patient-use). Other
`package terms include
`pharmacy bulk package
`
`and imaging bulk package.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` n/a
`
`
`
` n/a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` adequate
`
` adequate
`
` adequate
`
`
`
` adequate
`
`
`
` n/a
`
`
`
` n/a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v06
`
`
`
`
`
` Page 1
`
`
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Effective Date: February 1, 2019
`
`
`
`

`

`
`
` Item
`
`
`
`
`
` Assessor’s Comments
`
`
`
`
`
` 1.2 FULL PRESCRIBING INFORMATION
` 1.2.1 Section 2 (DOSAGE AND ADMINISTRATION)
`
`
` Information Provided
`
` in the NDA
`
` DOSAGE AND ADMINISTRATION section
`Apply EXSERVAN on
`
` Special instructions for
`
` product preparation (e.g.,
`
` top of the tongue
`where it adheres and
`reconstitution and resulting
`
`
` concentration, dilution,
` dissolves.
`Do not administer with
`
` compatible diluents,
`storage conditions needed
`liquids. As the film
`
` to maintain the stability of
`
` dissolves, saliva
`the reconstituted or diluted
`should be swallowed in
`
` product)
`a normal manner, but
`the patient should
`refrain from chewing,
`
` spitting or talking.
`
`
`
` adequate
`
`
`
`
`
` 1.2.2 Section 3 (DOSAGE FORMS AND STRENGTHS)
`
`
`
`OPQ-XOPQ-TEM-0001v06
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`
`
`
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` Page 2
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`
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`Reference ID: 4506982Reference ID: 4525554
`
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`
` Effective Date: February 1, 2019
`
`
`
`

`

`
`
` Assessor’s Comments
`
`
`
`
` adequate
`
` adequate
`
` n/a
`
`
`
` adequate
`
`
`
` n/a
`
`
`
` n/a
`
`orange, rectangular-
`shaped, orally
`dissolving film with
`“R50” printed in
` white on one side.
`
`
` n/a
`
`
`
` n/a
`
`Information
`
`Provided
`
` in the NDA
`
` DOSAGE FORMS AND STRENGTHS section
`
`
` Oral film
` Available dosage form(s)
` Strength(s) in metric system
`
`
`
` 50 mg
`If the active ingredient is a salt,
`
` n/a
`
` apply the USP Salt Policy per FDA
`
` Guidance
`A description of the identifying
`characteristics of the dosage
` forms, including shape, color,
`
` coating, scoring, and imprinting
`
`
`
` Item
`
`
`
`Assess if the tablet is scored. If
`product meets guidelines and
`criteria for a scored tablet, state
`
` “functionally scored ”
` For injectable drug products for
`
`parental administration, use
`appropriate labeling term (e.g.,
`single-dose, multiple-dose, single­
`
`patient-use). Other package type
`terms include pharmacy bulk
`package and imaging bulk
`
` package.
`
`
`
`OPQ-XOPQ-TEM-0001v06
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`
`
`
`
` Page 3
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`
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`
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`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Effective Date: February 1, 2019
`
`
`
`

`

`
`
`
`
`
` 1.2.3 Section 11 (DESCRIPTION)
`
` Information Provided
`
` in the NDA
`
`
`
` Item
`
`
`
`
`
` Assessor’s Comments
`
`
`
`
`
` DESCRIPTION section
`
`
`Proprietary and established
`
` name(s)
` Dosage form(s) and route(s)
`
` of administration
`If the active ingredient is a
`salt, apply the USP Salt
`Policy and include the
`
` equivalency statement per
`
` FDA Guidance.
`List names of all inactive
`
` ingredients. Use USP/NF
` names. Avoid Brand names.
`
`
` For parenteral injectable
` dosage forms, include the
`
`
` name and quantities of all
`inactive ingredients. For
`ingredients added to adjust
`the pH or make isotonic,
`include the name and
`
` statement of effect.
`If alcohol is present, must
`provide the amount of
`alcohol in terms of percent
`
` volume of absolute alcohol
`Statement of being sterile (if
`
` applicable)
` Pharmacological/
`
` therapeutic
`
`class
`Chemical name, structural
`
`formula, molecular weight
`If radioactive, statement of
`important nuclear
`
` characteristics.
`Other important chemical or
`physical properties (such as
`
` pKa or pH)
`
`
`
`
`
`
` Exservan (riluzole)
`
`
`
` Oral film
`
`
`
` n/a
`
`
` adequate
`
`
`
`
`
` adequate
`
`
`
` n/a
`
`Edited to meet this
`
` requirement.
`
`
`
` adequate
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`Riluzole is a member of
`
` the benzothiazole class.
`
`
`
` adequate
`
`
`
` They are present.
`
`
`
` adequate
`
`
`
` n/a
`
`
`
` n/a
`
`Appearance and
`solubility statements are
`
` included.
`
`
`
` adequate
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v06
`
`
`
`
`
`
`
`Reference ID: 4506982Reference ID: 4525554
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`
`
` Page 4
`
`
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`
` Effective Date: February 1, 2019
`
`
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`

`

` Section 11 (DESCRIPTION) Continued
`
`
` Information Provided
`
` in the NDA
`
`
`
` Item
`
`
`
`
`
` Assessor’s Comments
`
`
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`For oral prescription drug
`products, include gluten
`statement if applicable
`
`Remove statements that
`may be misleading or
`promotional (e.g.,
`“synthesized and developed
`
` by Drug Company X,”
`“structurally unique
`molecular entity”
`
`
`
`
`
`
`
`
`
`
`
` Item
`
`
`
`
`
`orange, rectangular-
`
` shaped film
`
`
`
` n/a
`
`
`
` 1.2.4 Section 16 (HOW SUPPLIED/STORAGE AND HANDLING)
`
` Information Provided
`
` in the NDA
` HOW SUPPLIED/STORAGE AND HANDLING section
`
` Available dosage form(s)
`
` Oral film
` Strength(s) in metric system 50 mg
`
`
`
` Carton of 60 pouches
`Available units (e.g., bottles
`
` of 100 tablets)
`Identification of dosage
`forms, e.g., shape, color,
`coating, scoring, imprinting,
`
` NDC number
`Assess if the tablet is scored.
`If product meets guidelines
`and criteria for a scored
`tablet, state “functionally
`
` scored”
`For injectable drug products
`for parental administration,
`
` use appropriate package
`type term (e.g., single-dose,
`multiple-dose, single-patient­
`use). Other package terms
`include pharmacy bulk
`package and imaging bulk
`
` package.
`
`
`
`
` Assessor’s Comments
`
`
`
`
` adequate
`
` adequate
`
` adequate
`
`
`
` adequate
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v06
`
`
`
`
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 5
`
`
`
`
`
` Effective Date: February 1, 2019
`
`

`

`
`
`Item
`
`
`
`
` Assessor’s Comments
`
`
` Section 16 (HOW SUPPLIED/STORAGE AND HANDLING) (Continued)
`
`
` Information Provided
`in the NDA
`
`Protect from bright
`
` light.
`
`
`
` Adequate
`
`
`
` n/a
`
`
`
` n/a
`
`20°C to 25°C (68°F to
`77°F); excursions
`permitted to 15°C to
`
` 30°C (59°F to 86°F)
`
` n/a
`
`
`
`
`
` adequate
`
`
`
` n/a
`
`Special handling about the
`supplied product (e.g.,
`protect from light,
`refrigerate). If there is a
` statement to “Dispense in
`
`original container,” provide
`
` reason why (e.g. to protect
`from light or moisture, to
`
` maintain stability, etc.)
`If the product contains a
` desiccant, ensure the size
`
`and shape differ from the
`dosage form and desiccant
`has a warning such as “Do
`
` not eat.”
`Storage conditions. Where
`
` applicable, use USP
`storage range rather than
`storage at a single
`
`temperature.
`Latex: If product does not
`contain latex and
`manufacturing of product
`and container did not
`
` include use of natural
`rubber latex or synthetic
`derivatives of natural rubber
`latex, state: “Not made with
`natural rubber latex. Avoid
`statements such as “latex­
`free.”
`
`Include information about
`
` child-resistant packaging
`
`
`
`
`
` adequate
`
`
`
` Effective Date: February 1, 2019
`
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v06
`
`
`
`
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 6
`
`
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Item
`
`
`
` Assessor’s Comments
`
`
`
`
` 1.2.5 Other Sections of Labeling
`
` 1.2.6 Manufacturing Information After Section 17 (for drug products)
`
` Information Provided
`
` in the NDA
`
` Manufacturing Information After Section 17
`
` Name and location of
`RILUTEK® is a registered
`trademark of Covis
`business (street address,
` Pharmaceuticals Inc.
`
`city, state and zip code) of
`the manufacturer, distributor,
`
` and/or packer
`
`
`
` adequate
`
`
`
` Manufactured by:
`
`
`
`
` Aquestive Therapeutics
`
` Warren, NJ 07059
`
`
`
`
` 2.0 PATIENT LABELING
`
`
`
`
`
`
`
`
`
` Assessment of Product Quality Related Aspects of Patient Labeling (e.g.,
`
` Medication Guide, Patient Information, Instructions for Use):
`
`The storage and used instruction discussed in the “Instruction for Use” is
`
`adequate from the CMC perspective.
`
`
` 3.0 CARTON AND CONTAINER LABELING
`
`3.1 Container Label
`
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v06
`
`
`
`
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
`
` Page 7
`
`
`
`
`
` Effective Date: February 1, 2019
`
`2 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately
`following this page
`
`

`

`
`
` Item
`
` Proprietary name,
`
`established name, and
`dosage form (font size and
`
` prominence
` Dosage strength
`
` Route of administration
`
`If the active ingredient is a
`salt, include the
`equivalency statement per
`
` FDA Guidance
`Net contents (e.g. tablet
`
` count)
`“Rx only” displayed on the
`
` principal display
`
`NDC number
`Lot number and expiration
`
`date
`Storage conditions. If
`applicable, include a space
`
` on the carton labeling for
`the user to write the new
`
` BUD.
`For injectable drug
`products for parental
`administration, use
`appropriate package type
`
` term (e.g., single-dose,
`multiple-dose, single­
`
` patient-use)
`Other package terms
`include pharmacy bulk
`package and imaging bulk
`package which require “Not
`for direct infusion”
`
` statement.
`If alcohol is present, must
`provide the amount of
`alcohol in terms of percent
`
` volume of absolute alcohol
`
` Bar code
`
`
`
` 50 mg
`
` Oral
`
` n/a
`
`
`
` 60 oral films
`
`
`
` Yes
`
`
` 10094-60
`
` Yes
`
` 20°C to 25°C (68°F to 77°F);
`
`excursions permitted to 15°C to
`
` 30°C (59°F to 86°F)
`
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` Yes
`
`OPQ-XOPQ-TEM-0001v06
`
`
`
`
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`Information Provided in the
`
` NDA
`
`
`
` Exservan (riluzole) oral film
`
` Assessor’s
`
`Comments about
`
` Carton Labeling
`
` Adequate
`
`
` Adequate
`
` Adequate
`
` n/a
`
`
`
` Adequate
`
`
`
` Adequate
`
`
` Adequate
`
` Adequate
`
`
`
` Adequate
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` Adequate
`
`
`
` Effective Date: February 1, 2019
`
`
`
` Page 10
`
`
`
`

`

`
`
` Item
`
`Information Provided in the
`
` NDA
`
`
` Aquestive Therapeutics, Warren,
`
` NJ 07059
`
` n/a
`
`
`
`
`
` n/a
`
`
`
` n/a
`
` Assessor’s
`
`Comments about
`
` Carton Labeling
`
` Adequate
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` n/a
`
`Name of
` manufacturer/distributor
`
`Medication Guide (if
`
` applicable)
`No text on Ferrule and Cap
`
` overseal
`When a drug product differs
`
` from the relevant USP
`standard of strength,
`quality, or purity, as
`determined by the
`
` application of the tests,
` procedures, and
`
` acceptance criteria set forth
`in the relevant
` compendium, its difference
`
`shall be plainly stated on its
`
` label.
`And others, if space is
`
` available
`
`
`
`
`
`
` n/a
`
`
`
` n/a
`
`
`
` Assessment of Carton and Container Labeling: Adequate
`
`
`
`
`1) Regarding the choice of term for describing the primary container closure: Per
`
`
`
` the data standard manuals:
`
` PACKET: An envelope into which only one dose of a drug product, usually
`
`
`
`
`
` in the form of granules or powder, has been directly placed. An example
`
`
`
`
`
`
` includes glassine powder paper containing aspirin. Other examples
`
`
` include aluminum foil packets into which alcohol swabs and pledgets are
`
`
`
`
` placed.
` POUCH: A flexible container used to protect or hold one or more doses of
`
`
`
`
` a drug product (e.g. a pouch into which oral contraceptive blister packs are
`
`
`
`
` inserted, and an overwrap pouch for large volume parenterals).
`
`
`
` Based on the above definitions, the packaging term “pouch” as proposed by the
`
`
`
` Applicant is appropriate. This is also in alignment with some of the other approved
`
` products for film dosage form.
`
`
`2) The “How To Use paragraph” on the carton has the following text: “Place film
`
`
`
`
`
`
` on top of tongue. Keep in place until film dissolves.”
`
`
`
`OPQ-XOPQ-TEM-0001v06
`
`
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`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
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` Page 11
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` Effective Date: February 1, 2019
`
`

`

`stays as a
` Technically, the film disintegrates and
`
`
`
`
`
`
`
`
` suspension in the mouth. Therefore, the term “disintegrates” could be better choice
` of word instead of “dissolves”. However, “disintegrates” could be confusing to the
`
`
`
` patients. Furthermore, recently approved product from the same Applicant (NDA
`
`
`
` 210833 for Clobazam Oral Film.) uses the same text as proposed for this film.
`
`
`
`
`
`
`
`
` Therefore, the text as proposed by the Applicant is acceptable.
`
`
`
`
`
`
` ITEMS FOR ADDITIONAL ASSESSMENT
`
` n/a
`
`
`
`
`
` Overall Assessment and Recommendation:
`
`Adequate
`
`
`
`
`
` Primary Labeling Assessor: Mariappan Chelliah
`
`
`
`
`
` Secondary Assessor: Wendy Wilson-Lee
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v06
`
`
`
`
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`
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` Page 12
`
`
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` Effective Date: February 1, 2019
`
`(b) (4)
`
`

`

`Mariappan
`Chelliah
`
`Wendy
`Wilson- Lee
`
`Digitally signed by Mariappan Chelliah
`Date: 10/11/2019 11:10:11AM
`GUID: 5399cb2c00032b7c21877aa0d4d5f794
`
`Digitally signed by Wendy Wilson- Lee
`Date: 10/11/2019 01:18:45PM
`GUID: 50816dbc000085595ca3284bbca465a8
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`25 Page(s) have been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`

`

`BIOPHARMACEUTICS
`
`
`
`
`
`
`
`Application No: NDA 212640; 505(b)(2)
`
`
`Drug Product Name/Strengths: Riluzole Oral Film/50 mg
`
`
`
`Route of Administration: Oral
`
`
`Indication: Treatment of Amyotrophic Lateral Sclerosis (ALS)
`
`
`
`
`Applicant Name: Aquestive Therapeutics
`
`
`Date of Submission: 01/31/2019 (Original)
`
`
`
`
`
`Primary Reviewer: Kaushalkumar Dave, Ph.D.
`
`
`
`Secondary Reviewer: Ta-Chen Wu, PhD
`
`
`
`
` REVIEW SUMMARY
`
` Submission: The proposed drug product, Riluzole Oral Film, 50 mg (designated as ROF by
`
`
`
`
` the Applicant during the development), is an orally dissolving (polymer based) film. This NDA
`is a 505(b)(2) submission which substantially relies on the prior safety and efficacy findings by
`
` the Agency for the Reference Listed Drug (RLD) Rilutek® tablets (NDA 020599, Covis
`
`
` Pharma) for the same indication ‘Treatment of Amyotrophic Lateral Sclerosis (ALS)’.
`
`
`
`
`
` Review Objective: The Biopharmaceutics review is focused on the evaluation of (1) the
` proposed dissolution method and acceptance criterion, and (2) formulation bridging.
`
`
`
`
` Dissolution Method: The Applicant conducted various studies and provided justifications for
`
`
`
`
`
` selection of the suitable dissolution testing conditions. The proposed dissolution method for
` the proposed Riluzole Oral Film 50 mg is as follows: 900 mL of 0.1N HCl using USP Apparatus
`
`
`
`
`
` 1 (basket) at 50 rpm. The Applicant prepared several test batches to investigate the
`
`
`
`
` discriminating ability of the proposed product. The provided dissolution data show that the
`
`
`
`
` proposed dissolution method can discriminate between the target product and the deviant batch
`
`
` content. However, the proposed method could not discriminate
`
`
`
`prepared with
` between the target and other deviant batches prepared with altered composition and process
`
`
`
`
`
`
` parameters. Considering that the proposed product is designed to disintegrate very rapidly, and
`
`
`
` that the drug substance has high solubility in the proposed dissolution medium, it is challenging
`
`
`
` to develop a discriminating dissolution method. Based on the Applicant’s appropriate selection
`
`
` of the dissolution testing conditions, and the provided data demonstrating some discriminating
`
`
` ability, the proposed dissolution method is deemed adequate for quality control testing of the
`
`
` proposed product.
`
`
`
` Dissolution Acceptance Criterion: Based on the provided full profile dissolution data from
`
`
` the clinical and registration batches, the Applicant’s originally proposed dissolution acceptance
`
` ’ was deemed permissive and, therefore, not
`
`
`
`
`criterion of ‘
` acceptable. Note that the provided profile data from discriminating ability studies indicate that
`
`
`
` the proposed dissolution method is likely to be more discriminating and thus be able to identify
`
`
`
`
`
`
` potential quality issue with setting of dissolution acceptance criterion of ‘NLT % (Q) at 20
`
`
`
`
`
`
`
` minutes’ than with the currently proposed dissolution acceptance criterion of ‘
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4506982Reference ID: 4525554
`
`1
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

` ’. Therefore, the
`
`
`
` Applicant was recommended to implement the dissolution
`acceptance criterion of ‘NLT
`
` % (Q) at 20 minutes’ for quality control testing of the proposed
`
`
`
` product. The Applicant agreed to the FDA’s recommendation and revised the dissolution
`
`
` acceptance criterion accordingly.
`
`
`
`
`
`
` The final and approved dissolution method and agreed-upon acceptance criterion for the quality
` control of the proposed drug product at batch release and during stability testing are as follows:
`
`
`
`
`
`
`FDA approved dissolution method and acceptance criterion for the proposed product
`
` USP Apparatus 1 (Basket)
`
`
`
` Apparatus
`
`
`
`
`
`
`
`
`
` Paddle Speed
`
`
`
` Volume
`
`
`
` Medium
`
`
`
` Temperature
`
`
`
` 50 rpm
`
`
`
` 900 mL
`
`
`
` 0.1N HCl
`
`
`
` 37.0 ± 0.5 C
`
`
`
` Acceptance Criterion
`
`
`
` NLT % (Q) at 20 minutes
`
`
`
` Formulation Bridging: In-vitro or in-vivo bridging study is not needed for the proposed
`
`
`
`
`
`
`
` product, as there were no changes made in (i) composition for the clinical batches, exhibit
`
` batches, and proposed commercial drug product, (ii) product manufacturing site, and (iii)
`
`
` manufacturing process in the scale-up.
`
`
` RECOMMENDATION:
`
` From a Biopharmaceutics perspective, NDA 212640 for Riluzole Oral Film, 50 mg, is adequate
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` and recommended for APPROVAL.
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`Reference ID: 4506982Reference ID: 4525554
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`2
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`
`
`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
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`

`

`
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` BIOPHARMACEUTICS ASSESSMENT
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`
` LIST OF SUBMISSIONS REVIEWED
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` Submissions Reviewed
`
`eCTD
`Received
`
`
` sequence #
` date
`
` 01/31/2019
`
` 0001
`
` 05/13/2019
`
` 0003
`
` 09/05/2019
`
` 0007
`
` 10/01/2019
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` 0009
`
` 10/07/2019
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` 0010
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`
`
` Document
`
` Original NDA Submission
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`
`
` Quality/Response to Information Request
`
` Quality/Response to Information Request
`
` Quality/Response to Information Request
`
` Quality/Response to Information Request
`
`
`
`
` BACKGROUND
`
` The proposed drug product, Riluzole Oral Film, 50 mg (designated as ROF by the Applicant
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`
`
`
` during the development), i