CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208082Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`Recommendation: Approve
`
`NDA 208082
`
`Review 2
`
`
`
`
`‘ Drug Name/Dosage Form
`SD-809 Austedo (deutetrabenazine)
`Strength
`6 mg, 9 mg, 12 mg
`Route of Administration
`
`‘
`
`N/A
`
`Rx/OTC Dispensed
`
`Applicant
`
`Teva Pharmaceuticals, Inc.
`
`US agent, if applicable
`
`
`
`DISCIPLINE
`
`REVIEWER
`
`BRANCH/DIVISION
`
`Quality Review Team
`
`Drug Substance
`Gene Holbert
`Branchl/DNDAPI/ONDP
`
`Drug Product
`Martha Heimann
`Branch l/DNDP l/ONDP
`
`Process
`N/A
`
`Microbiology
`
`Facility
`
`Biopharmaceutics
`Regulam Busmess
`Process Manager
`
`N/A
`
`Wayne Seifert
`
`N/A
`Dahlia Woody
`
`Application Technical Lead Martha Heimann
`
`Submissions Reviewed
`
`Branchl/DIA/OPF
`
`Branch 1/DRBPM1/OPRO
`
`Branch l/DNDP l/ONDP
`
`
`
`
`
`DISCIPLINE(S) AFFECTED
`DOCUNIENT DATE
`SUBMISSION
`
`April 14, 2016
`Drug Substance
`
`Drug Product
`
`May 09, 2016
`
`Drug Substance, Drug Product
`
`October 3, 2016
`
`

`

`QUALITY ASSESSNIENT
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUNIENTS:
`
`A. DMFs:
`
`Refer to Overall Quality Assessment. Review No. 1, dated April 26, 2016.
`
`B. Other Documents: IND, RLD, or sister applications
`
`
`
`APPLICATION
`NUMBER
`
`112975
`
`21894
`
`
`
`DESCRIPTION
`
`Development of deutetrabenazine for Huntington’s
`disease.
`
`(D) (4)
`
`Approved NDA for Xenazine® (telrabenazine) tablets
`currently held by Valeant Pharmaceuticals.
`Reference drug for 505(b)(2) submission.
`
`(b) (4)
`
`
`
`DOCUMENT
`
`IND
`
`IND
`
`NDA
`
`NDA
`
`2. CONSULTS:
`
`
`
`
`
`
`
` DISCIPLINE STATUS RECOMlVlENDATION DATE REVIEWER
`
`
`
` N/A
`
`Pharmacology/Toxicology
`
`cm -—-
`————
`_——-
`
`N/A
`
`N/A
`
`NDA 208082 Resubmission
`
`Page 2
`
`3/7/2017
`
`

`

`
`
`Executive Summary
`
`1. Recommendations and Conclusion on Approvability
`
`From a quality perspective, approval of NDA 208082 is recommended. The applicant
`has adequately addressed the outstanding deficiencies from the original review.
`
`11. Summary of Quality Assessments
`
`A. Product Overview
`
`Deutetrabenazine (TBZ-ds) (l) is a new chemical entity indicated for treatment of
`chorea associated with Huntington’s disease (HD). Chemically, deutetrabenazine
`is an analog of an approved drug, tetrabenazine (TBZ) (2) in which the hydrogen
`atoms at the 9- and lO-methoxy (-OCH3) substituents of tetrabenazine are
`replaced by deuterium. Both deutetrabenazine and tetrabenazine are racemic
`mixtures. The absolute stereochemistry of the 312,1le enantiomers is shown in
`the figures below.
`
`03cc
`
`oaco
`
`H
`
`O
`
`l: Deutetrabenazine
`
`
`
`NDA 208082 Resubmission
`
`Page 3
`
`3/7/2017
`
`

`

`QUALITY ASSESSNIENT
`
`Deutetrabenazine tablets are round, MW-coated tablets containing 6 mg, 9 mg, or
`12 mg deutetrabenazine. Deutetrabenazine tablets contain excipients, and have
`physical characteristics, such as dissolution profile, that are characteristic of
`extended-release products. However, the applicant is not seeking an extended-
`release claim and did not submit data to support such a claim.
`
`
`
`
`Proprietary Name of the Drug Austedo is proposed Product
`
`Non Proprietary Name of the
`Drug Product
`
`Non Proprietary Name of the
`Drug Substance
`
`Deutctrabenazine Tablets
`
`Deutetrabenazine
`
`Proposed Indication(s) including
`Treatment of chorea associated with
`Intended Patient Population
`Huntington’s disease
`
`Duration of Treatment
`Chronic
`
`Maximum Daily Dose
`
`Alternative Methods of
`Administration
`
`48 mg
`
`None
`
`
`
`
`
`B. Quality Assessment Overview
`
`The OPQ review team identified one major deficiency related to control of the
`bulk drug substance, and two minor deficiencies. The applicant addressed the
`deficiencies in the resubmission. There are no other CMC changes.
`
`Drug Substance
`
`The drug substance specification submitted in the original NDA -did not include a
`(mo
`test for
`, a known genotoxic substance used in manufacture
`of deutetrabenazine. The applicant submitted a validated GC method for
`determination of
`M“) in the drug substance.
`
`Drug Product
`
`The applicant submitted a revised post—approval stability protocol that includes
`placing the first three commercial batches on long-term and accelerated stability
`studies, and withdrawing and/or discussing any out of specification batches with
`the Agency. The applicant also revised the claim for categorical exclusion from
`environmental assessment to include a statement that to Teva’s knowledge, no
`extraordinary circumstances exist.
`
`Facilities
`
`AH facilities proposed for manufacture and testing of deutetrabenazine and
`Austedo (deutetrabenazine) tablets are currently acceptable.
`
`NDA 208082 Resubmission
`
`Page 4
`
`3/7/2017
`
`

`

`QUALITY ASSESSNIENT
`
`C. Novel Approaches
`
`The applicant did not employ any novel approaches.
`
`D. Any Special Product Quality Labeling Recommendations
`
`There are no special labeling recommendations.
`
`E. Life Cycle Knowledge Information/Final Risk Assessment
`
`See Attachment 1.
`
`10 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`NDA 208082 Resubmission
`
`Page 5
`
`3/7/2017
`
`

`

`-.A-n m V-.‘-—
`
`mm.)
`
`him-inhuman- ‘
`
`1.14 Labeling
`
`Immediate Container Label
`
`
`
`Reviewer’s Assessment: The proposed container label is acceptable, from a CMC perspective,
`with one minor chan . The
`Patient Information insert includes an instruction to
`
`However,
`container labels and Section 16 of the PI (How Supplied/Storage Id Handling) do not contain
`corresponding language. The drafi PI has been revised to include the statement “Protect from
`light and moisture.” The applicant has agreed to add the same statement to the container labels
`once labeling recommendations from OSE/DMEPA are available.
`
`Carton Labeling
`
`Not applicable.
`
`Primary Drug Product/Labeling Reviewer: Martha R. Heimann, PILD.
`
`Secondary Reviewer Name): Wendy I. Wilson-Lee, PILD.
`
`

`

`Martha
`Heimann
`
`Wendy
`Wilson- Lee
`
`Digitally signed by Martha Heimann
`Date: 3/01/2017 05:45:36PM
`GUID: 504f845f00000ed260627d268a8cdc9d
`
`Digitally signed by Wendy Wilson- Lee
`Date: 3/02/2017 10:24:33AM
`GUID: 50816dbc000085595ca3284bbca465a8
`
`6 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`ATTACI-INIENT 1
`
`Final Risk Assessment for NBA 208082
`
`Deutetrabenazine Tablets
`
`From Initial Risk Identification
`
`Use 0
`lmderstan
`
`process with adequate
`g 0 process variables from-.
`
`Microbial evaluation of stability samples did
`not show evidence of microbial growth.
`
`
`
`Assay, Stability
`
`Impurities due to:
`excipient reactions,
`
`.
`how dose, particle
`tio
`Size/shape, se
`grega
`n,
`
`Formulation, process
`
`Content uniformity
`6 mg tablet
`Content uniformity
`9 mg, 12 mg tablets
`
`Physical (solid state)
`stability
`
`Microbial limits
`
`Formulation, solubility
`Alcohol dose dumping of—
`excipient and/or API
`
`Particle size,-
`,size, shape,
`coat, formulation,
`process parameters
`
`H InVllI‘O£50lestudies
`
`t alcohol does not affect drug
`
`onstrate
`release.
`
`Dissolution method is discriminating with
`respectto
`
`do
`
`not have a large impact on the dissolution
`profile of the SD-809 tablets, the current
`dissolution method is capable of idmtifying
`trends in these variables.
`
`*Risk ranking applies to product attribute/CQA
`“For example, critical controls, underlying control strategies assumptions, post marketing commitment, knowledge management post approval, etc.
`
`

`

`Martha
`Heimann
`
`Digitally signed by Martha Heimann
`Date: 3/07/2017 02:36:40PM
`GUID: 504f845f00000ed260627d268a8cdc9d
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Martha
`Heimann
`
`Digitally signed by Martha Heimann
`Date: 3/07/2017 02:54:09PM
`GUID: 504f845f00000ed260627d268a8cdc9d
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`.5
`er
`
`s
`
`:3 fl/é DEPARTMENTOFHEALTH&HUMANSERVICES
`
`' "a
`"We“:
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville MD 20857
`
`MEMORANDUM
`
`Date:
`
`May 24, 2016
`
`From:
`
`Martha R. Heimann, Ph.D., CMC Lead, OPQ/ONDP and ATL for NDA 208082
`
`To:
`
`NDA 208082
`
`Subject: Manufacturing Facility Status and Complete Response (CR) Recommendation for
`NDA 208082, Austedo (deutetrabenazine) Tablets
`
`This memorandum is an addendum to the Office of Pharmaceutical Quality (OPQ) integrated
`review for NDA 208082 dated April 20, 2016. At the time the original review was completed,
`the review team determined that outstanding quality issues would preclude approval. However,
`the overall facility recommendation was still pending.
`
`Per the Overall Manufacturing Inspection Recommendation (Wayne Seifert, May 24, 2016), all
`manufacturing facilities are considered acceptable. Thus, there are no facility related
`deficiencies for the CR letter. Due to the unresolved deficiencies detailed in the April 20, 2016,
`OPQ still recommends a CR action for NDA 208082.
`
`Digitally signed by Martha R. Heimann —S
`M a rt h a R .
`DN: mus, o=US. Govemment, ou=HHS,
`ou=FDA, ou=People.
`O
`o.9.2342.19200300.100.1.l=1300091527,
`n=Martha R. H '
`—5
`_
`He I ma n n S 3......2msmm
`
`

`

`NDA 208082 OPQ Review Addendum
`
`
`
` .--..~:-...~w-..-..-...... l ..
`
`
`
`
`
`
`
`
`
`
`

`

`QUALITY ASSESSMENT
`
`Recommendation: Complete Response
`
`NDA 208082
`
`Review 1
`
`April 18, 2016
`
`Drug Name/Dosage Form
`
`SD—809 Austedo (deutetrabenazine)
`
`6 mg, 9 mg, 12 mg
`Strength
`
`Route of Administration
`
` US agent, if applicable
`
`Rx/OTC Dispensed
`
`Rx
`
`Applicant
`
`Teva Pharmaceuticals, Inc.
`
`
`Quality Review Team
`
`DISCIPLINE
`
`REVIEWER
`
`BRANCH/DIVISION
`
`_—
`
`
`Facility
`Don Obenhuber
`Branchl/DIA/OPF
`
`Biopharmaceutics
`Jing Li
`Branch l/DB/ONDP
`
`Branch l/DRBPMl/OPRO
`
`Regulatory Business
`Process Manager
`
`Dahlia Woody
`
`Application Technical Lead Martha Heimann
`
`Branch l/DNDP l/ONDP
`
`OPQ-XOPQ-NDA 208082
`
`

`

`CHENIISTRY REVIEW
`
`SUBMISSION
`
`DOCUMENT DATE
`
`Submissions Reviewed
`
`
`Original NDA
`5/29/2015
`All
`
`Biopharmaceutics
`
`11/2/2015
`
`Process
`
`
`
`Response to IR
`
`Response tom
`
`Response to IR
`
`cycle teleconference
`
`Response to IR
`
`Response to IR
`
`1/15/2016
`
`2/22/2016
`
`Drug Substance
`
`Drug Substance
`
`Submissions Not Reviewed
`
`The 4/14/2016 amendment contains a partial response to the 2/17/2016 information
`request regarding controls for
`M“) in the drug substance. The applicant
`submitted a revised specification and analytical procedure. However, per the applicant’s
`cover letter the supporting method validation report is not complete. The amendment also
`contains a response to the 4/ 12/2016 request for revisions to the drug product post-
`approval stability commitment.
`
`APPEARS THIS WAY ON ORIGINAL
`
`2
`
`OPQ-XOPQ-NDA 208082
`
`

`

`am an >m Eun- m m.
`
`QUALITY ASSESSNIENT
`
`NDA 208082
`
`Table of Contents
`
`Table of Contents .....................................................................................................3
`
`Quality Review Data Sheet......................................................................................4
`
`Executive Summary .................................................................................................5
`
`Primary Quality Review ........................................................................................ 11
`
`ASSESSMENT OF THE DRUG SUBSTANCE ....................................................................... 11
`
`2.3.8
`
`DRUG SUBSTANCE ......................................................................................... 11
`
`ASSESSMENT OF THE DRUG PRODUCT ........................................................................... 70
`
`2.3.P
`
`DRUG PRODUCT .............................................................................................. 70
`
`R2
`
`Comparability Protocols ......................................................................................91
`
`ASSESSMENT OF THE PROCESS..........................................................................................92
`
`2.3.P
`
`DRUG PRODUCT .............................................................................................. 92
`
`R2
`
`Comparability Protocols .................................................................................... 128
`
`ASSESSMENT OF THE FACILITIES ................................................................................... 132
`
`2.3.8
`
`2.3.P
`
`DRUG SUBSTANCE ....................................................................................... 132
`
`DRUG PRODUCT ............................................................................................ 134
`
`ASSESSMENT OF THE BIOPHARMACEUTICS ............................................................... 138
`
`ASSESSMENT OF MICROBIOLOGY .................................................................................. 151
`
`ASSESSMENT OF ENVIRONMENTAL ANALYSIS .......................................................... 152
`
`I.
`
`Review of Common Technical Document—Quality (CTD-Q) Module 1 Labeling &
`Package Insert ................................................................................................................ 153
`
`H.
`
`List of Deficiencies To Be Communicated ................................................................... 161
`
`IH.
`
`Attachments .................................................................................................................... 163
`
`3
`
`OPQ-XOPQ-NDA 208082
`
`

`

`QUALITY ASSESSNIENT a.“ n. )u) Eum m m.
`
`NDA 208082
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUNIENTS:
`
`A. DMFs:
`
`ITEM
`REFERENCED
`
`Type IV
`
`Type III
`
`Type HI
`
`
`
`1 Adequate information provided in application
`
`B. Other Documents: IND, RLD, or sister applications
`
`
`DOCUMENT
`APPLICATION NUMBER
`DESCRIPTION
`
`
`
`Approved NDA for Xenazine® (tetrabenazine)
`tablets currently held by Valeant Pharmaceuticals.
`Reference drug for 505(b)(2) submission.
`
`2. CONSULTS:
`
`
`DISCIPLINE
`STATUS
`RECOMMENDATION
`DATE
`
`
`
`_-—-W
`_-—--
`N/A_-—--
`
`
`
`CDRH
`
`Clinical
`
`N/A
`
`4
`
`OPQ-XOPQ-NDA 208082
`
`

`

`QUALITY ASSESSNIENT
`
`NDA 208082
`
`Executive Summary
`
`Recommendations
`
`Recommendation and Conclusion on Approvability
`
`From a quality perspective, NDA 208082 is not recommended for approval in its current
`form. The applicant must adequately address the following deficiencies prior to approval
`of the application.
`
`Drug Substance
`
`The primary review deficiency is the lack of adequate controls for deutetrabenazine drug
`substance. The drug substance specification submitted in the original NDA does not
`include a control for a potential genotoxic impurity,
`M“) which is used in the
`manufacture of deutetrabenazine. In the 22-Feb-2016 amendment, the applicant
`committed to adding a test and acceptance criterion of not more than
`(ppm)
`out), and amending the NDA with this test, acceptance criteria, and
`method validation information on or before 22-Mar-2016. The 14-Apr-2016 amendment
`contains a revised specification and the proposed analytical procedure, but the applicant
`indicated the supporting method validation report is not available yet. The proposed
`acceptance criterion for
`M“) is lower than the threshold for toxicological
`concern (TTC) based on the maximum recommended dose of deutetrabenazine.
`However, in the absence of the method validation report, the adequacy of the test cannot
`be evaluated and review of the 14-Apr-2016 amendment is deferred to the next review
`cycle.
`
`(“(0
`
`Drug Product
`
`The standard post—approval stability commitment for new applications includes placing
`the first three commercial batches on stability under long—term (25°C/60% R. H.) and
`accelerated (40°C/75% R. H.) conditions unless the primary stability batches submitted in
`the NDA were manufactured at full commercial scale. The stability batches submitted in
`the NDA were not manufactured at commercial scale; therefore, the applicant was asked
`to revise the post-approval to include the first three commercial batches. The applicant
`responded in the 14-Apr-2016 amendment. As review of that amendment is deferred, the
`response will be evaluated in the next review cycle.
`
`Environmental Assessment/Categorical Exclusion
`
`The applicant has claimed a categorical exclusion under 21 CFR §25.3l(b). Approval of
`the NDA would increase the use of the active moiety, but the estimated concentration of
`deutetrabenazine at the point of entry into the aquatic environment is below 1 part per
`billion (ppb). However, the applicant did not confirm that there are no extraordinary
`
`OPQ-XOPQ-NDA 208082
`
`

`

`QUALITY ASSESSNIENT
`
`NDA 208082
`
`circumstances (information to indicate that approval of the NDA would adversely affect
`the environment), which is required to support the claim for categorical exclusion.
`
`In addition to the deficiencies cited above, the overall manufacturing facility
`recommendation is still pending. The overall recommendation will be entered into
`Panorama once completed. An “Acceptable” facility recommendation will not affect the
`final OPQ recommendation. However, a “Withhold” recommendation would require
`inclusion of standard language inspections in the action letter.
`
`. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`There are no Phase 4 commitments or agreements. The OPQ review team did not
`identify any issues that would require risk management steps.
`
`Summary of Quality Assessments
`
`Currently, the only drug approved in the US for treatment of chorea associated with
`Huntington’s disease (HD) is Xenazine (tetrabenazine) (l), a vesicular monoamine
`transporter, type 2 (VMAT2) inhibitor. By selectively inhibiting VMAT2 in the central
`nervous system, tetrabenazine depletes presynaptic monoamines, including dopamine,
`and decreases chorea in patients with HD. Tetrabenazine is rapidly metabolized in vivo
`to a— and B- isomers of dihydrotetrabenazine (HTBZ) (2), which provide systemic
`exposure for pharmacological activity. However, rapid metabolism of (1-HTBZ and
`B-HTBZ by CYP2D6 to the 9- and lO—O—desmethyl metabolites (3 and 4) results in large
`fluctuations in plasma concentrations and the need for frequent dosing.
`
`H'3CO
`
`H
`
`360
`
`
`..
`
`
`0
`
`ED
`
`H300
`
`H300
`
`H
`
`N
`
`0H
`
`R10
`
`R20
`
`I::>
`
`H
`
`N
`
`OH
`
`1: HTBZ"
`
`2: u—lli—HTBZ
`
`3: 9-0-desmethyl. R1: H. R2 = H3C
`4:
`lO-O-desmethyl. R1: ch. R2 = H
`
`* Tetrabenazine is a racemic mixture. The absolute stereochemistry of the 3R..1 le enantiomer is shown.
`
`The applicant proposes use of a deuterated analog of tetrabenazine, (d6)-tetrabenazine or
`deutetrabenazine (5) for treatment of chorea associated with HD.
`
`0300
`
`0300
`
`O
`
`5: Deutetrabenazine
`
`OPQ-XOPQ-NDA 208082
`
`

`

`QUALITY ASSESSNIENT
`
`NDA 208082
`
`(m4)
`
`A. Drug Substance Quality Summary for Deutetrabenazine
`
`Deutetrabenazine [chemical name: (RR, SS)—l,3,4,6,7,1 1b—hexahydro—9,10—di(methoxy—
`d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-Z-one] was developed by Auspex
`Pharmaceuticals (now part of Teva Pharmaceuticals). It is a well characterized small
`molecule with molecular formula C19H21D6N03 and molecular weight 323.46. There are
`two chiral centers present; however, the drug substance is a racemic mixture.
`Deutetrabenazine is a moderately lipophilic molecule (Log P 2.88) with pH dependent
`solubility. It is poorly soluble in water (< 0.05 mg/mL). Solubility increases at lower
`pH, with maximum solubility (8.2 mg/mL) at pH 3.
`
`The applicant has identified two polymorphic forms of deutetrabenazine, which were
`'
`4
`characterized.
`(m )
`mm
`
`The applicant has adequately characterized the drug substance by
`(law) All results from spectroscopic studies and
`physicochemical analyses are consistent with the proposed structure and route of
`synthesis.
`
`mm)
`
`Deutetrabenazine is manufactured for the applicant by
`
`0’) (4)
`
`(b) (4)
`
`The applicant has developed and implemented adequate control procedures for starting
`materials, in—process testing, and
`(ow) to ensure the quality of the
`finished drug substance. The applicant has also thoroughly characterized potential
`process impurities.
`
`The drug substance specification includes appropriate tests for critical quality attributes
`(CQAs) such as appearance, identity, assay, related substances, residual solvents, and
`elemental impurities. The applicant has provided adequate characterization of related
`substances and justification for the proposed acceptance criteria. The analytical
`procedures for these parameters are
`M")
`m“). Non-compendial analytical methods for assay, related substances, and
`mm are validated for critical analytical parameters such as linearity, specificity,
`precision, accuracy, solution stability, and robustness, and are suitable for their intended
`use. However, the specification submitted in the original NDA does not include a test for
`(mm a known genotoxic substance used in manufacture of
`
`(I!) (4)
`
`7
`
`OPQ-XOPQ-NDA 208082
`
`

`

`QUALITY ASSESSNIENT
`
`NDA 208082
`
`deutetrabenazine. In response to an information request, the applicant proposed a test
`method and acceptance criterion for
`mm but has not submitted the validation
`report needed to support suitability of the test method.
`
`(I!) (4)
`
`. Drug Product Quality Summary for Deutetrabenazine Tablets
`
`Deutetrabenazine tablets are round. mmcoated tablets containing 6 mg, 9 mg, or 12 mg
`deutetrabenazine. The tablet
`(m4) contain mannitol
`(m4), microcrystalline cellulose,
`povidone
`(mm, polysorbate 80,
`(m4), polyethylene oxide,
`magnesium stearate, butylated hydroxvanisole, and butvlated hvdroxvtoluerre.
`
`(b) (4)
`(b) (4)
`
`The individual strengths are differentiated by
`
`coat color and imprint as follows:
`
`(b) (4)
`
`6 mg: purple tablets with “SD” over “6” printed on one side
`9 mg: blue tablets with “SD” over “9” printed on one side
`12 mg beige tablets with “SD” over “12” printed on one side
`
`Deutetrabenazine tablets will be manufacture by
`(m4)
`.-
`.
`-
`. The manufactur mg process involves
`
`0» (4)
`
`(B) (4) _
`(b) (4)
`
`(b) (4)
`
`. The tablets are
`
`(b) (4)
`
`coated
`
`“”W The manufactlu'er has adequately identified critical process parameters
`and material attributes that would impact the drug product C QAs.
`
`(”(4) have physical
`Deutetrabenazine tablets
`characteristics, such as dissolution profile, that are characteristic of extended-release
`products. However, dlu‘ing review of the application, the review team noted that the
`proposed product labeling does not include an extended-release claim.
`
`(”(4)
`(b) (4)
`
`applicant is not seeking an extended-release claim.
`(”(4), the product will be labeled simply as “tablets”.
`
`(wet)
`
`(IN)
`
`M4) As the
`(b) (4)
`
`The specifications for deutetrabenazine tablets include appropriate tests CQAs such as
`including appearance, identification by IR and HPLC, assay, dissolution, related
`substances impru‘ities, content 1mifonnity, and
`(ma) assay. All
`analytical procedm‘es are adequately described and validated.
`
`OPQ-XOPQ-NDA 208082
`
`

`

`QUALITY ASSESSNIENT a.“ m )u) Eum m m.
`
`NDA 208082
`
`(no)
`
`Deutetrabenazine tablets are packaged in 60-count,
`with a
`
`HDPE bottles
`one
`mu) closure
`(no). Based on the stability data provided, an expiration dating period of
`32 months is acceptable when stored at 25°C.
`
`C. Summary of Drug Product Intended Use
`
`Austedo is unro o sed
`Pro a rietarv Name of the Dru_ Product
`Deutetrabenazine Tablets
`Non Pro u rietarv Name of the Dru_ Product
`Non Pro u rietai Name of the Dru_ Substance Deutetrabenazine
`Proposed Indication(s) including Intended
`Treatment of chorea associated with
`Patient Po n ulation
`Huntin {ton’s disease
`Duration of Treatment
`Chronic
`
`None
`
`Maximum Dail ' Dose
`Alternative Methods of Administration
`
`48 my
`
`D. Biopharmaceutics Considerations
`1. BC S Classification:
`
`0 Drug Substance: Not established.
`0 Drug Product: Not established.
`
`2. Biowaivers/Biostudies
`
`o Biowaiver Requests. None.
`0 PK studies: The PK studies will be reviewed by the Office of Clinical
`Pharmacology.
`
`The proposed in vitro dissolution method for SD-809 Austedo (deutetrabenazine) Tablet
`is acceptable. The selection of the apparatus and testing conditions was justified, and the
`dissolution method was adequately validated. The proposed dissolution acceptance
`criteria are acceptable and supported by the data on the clinical and the registration
`batches. The phase 1 formulation and the to-be—marketed formulation were adequately
`bridged. Therefore, NDA 208082 is recommended for APPROVAL from a
`Biopharmaceutics perspective.
`
`E. Novel Approaches
`
`The applicant did not employ any novel approaches.
`
`F. Any Special Product Quality Labeling Recommendations
`
`There are no special labeling recommendations,
`
`G. Life Cycle Knowledge Information (see Attachment A)
`
`9
`
`OPQ-XOPQ-NDA 208082
`
`

`

` QUALITY ASSESSMENT
`
`NDA 208082
`
`OVERALL ASSESSMENT AND SIGNATURES: EXECUTIVE SUMMARY
`
`
`
`10
`
`OPQ-XOPQ-NDA 208082
`
`

`

`QUALITY ASSESSMENT
`
`NDA 208082
`
`ASSESSNIENT OF THE BIOPHARNIACEUTICS
`
`38. Are the in—vitro dissolution test and acceptance criteria adequate for assuring quality
`control and consistent bioavailability of the drug product?
`
`Yes. The in vitro dissolution method is acceptable. The selection of the apparatus and testing
`conditions was justified. The dissolution method was adequately validated.
`The proposed dissolution acceptance criteria are acceptable and supported by the data on the
`clinical and the registration batches.
`
`The Biopharmaceutics review is focused on the following aspects:
`— Solubility of the drug substance
`— Drug product formulation
`
`— Dissolution method and method development
`— Effect of alcohol on in vitro dissolution
`
`— Dissolution acceptance criterion
`— Rationale for absence of extended release claim
`
`— Bridging of different formulations and scales
`
`38.1. Solubility:
`
`The aqueous solubility of the drug substance, deutetrabenazine, is high in acidic conditions, and
`the solubility is pH dependent, as shown in Figure 38-1.
`
`'\Mym,1“er|
`
`(mI
`
`1
`
`DH
`
`Figure 38—1 Deutetrabenazine solubility profile as a function of pH
`
`38.2. Formulation:
`
`Deutetrabenazine is formulated in 6, 9 and 12 mg tablets for oral administration. The SD-809
`Tablets were formulated to provide a
`mu) profile in the low pH region of the
`digestive tract, the stomach and upper gastrointestinal region, where deutetrabenazine would
`achieve its maximum potential for solubility.
`The composition of the formulation is shown in Table 38-1.
`
`mm (b) (4)
`
`138
`
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`
`

`

` " ""5
`QUALITY ASSESSMENT
`V“"""
`Imam:
`
`NDA 208082
`
`
`
`Table 38-1 SD-809 Tablet Composition
`meerwmmm standard/evade
`Deutetrabenazine m-m Active ingredient
`In-houselGMP
`
`Polysorbate 80
`
`Microcrystalline Cellulose Povidone .
`
`
`38.3. Dissolution Method and Method Development
`
`Table 38-2 shows the conditions employed for the dissolution method.
`
`Table 38-2 Dissolution method for SD-809 Tablets
`
`Apparatus 2 over a disk
`
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`

`QUALITY ASSESSMENT
`
`
`
`Reviewer’s Assessment:
`
`SD-809 (deutetrabenazine; d6-tetrabenazine; AustedoTM) is a centrally-acting drug
`indicated for the treatment of chorea in Huntington’s disease (I-ID). The SD-809 tablets
`are designed to deliver the drug to the upper gastrointestinal. The final commercial SD-
`809 dosage form is formulated in 6 mg, 9 mg, or 12 mg tablets for oral administration.
`Daily doses of SD-809 are proposed to be administered with food and range from 6 mg
`to 48 mg, with daily doses of 12 mg and higher given as two divided doses.
`As the drug product is designed to release the drug in the stomach, an acidic medium of
`pH 3.0, where the drug substance has good solubility, was chosen for dissolution. The
`selection of the apparatus and the medium volume were justified. The method was
`adequately validated.
`The discriminating ability of the dissolution method was demonstrated b utilizin
`tablets that were intentional] manufactured
`
`ou
`
`process c anges
`
`e SD—809 ta ets,
`sso ution pro e o
`identifying trends in these variables.
`
`do not have a large impact on the
`e current dissolution method is capable of
`
`No alcohol induced dose dumping was observed.
`Overall the dissolution method has been evaluated and found acc table.
`
`143
`
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`
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`

` FHA!“
`
`QUALITY ASSESSMENT
`
`fPAEn
`
`NDA 208082
`
`38.4. Dissolution Acceptance Criteria:
`
`The proposed acceptance criteria are shown in Table 38—3.
`
`Table 38-3. Proposed dissolution acceptance criteria for SD-809 tablets
`
`
`
`In order to evaluate the adequacy of the proposed acceptance criteria, the following IR was
`communicated to request the raw data for the clinical and registration batches in the 74-day letter
`dated August 10, 2015.
`
`Provide the complete dissolution profile data (individual, mean, SD, profiles)for the pivotal
`clinical batch and the primary stability batches in ".xpt"format. Include dissolution data at all
`the sampling time points in addition to the speafication time points.
`
`This Reviewer plotted the mean dissolution profiles for all the clinical (N451173A, N452166B,
`N45 1 737A, N452168B, N451 174A, N452167B) and stability batches at various storage time
`periods, based on the data provided by the Sponsor on September 4, 2015.
`m4
`MONTH=3
`
`
`
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`

`QUALITY ASSESSMENT
`
`NDA 208082
`
`
`
`
`Figure 38-8. The mean dissolution profiles of the clinical and registration batches
`
`The data appear to support the proposed acceptance criterion. However, only the dissolution data
`at l, 2, and 5 hours were
`vided. The data seem to suggest that a fighter limit for the final
`sampling time (e.g., NLT
`in 4 hr) may be appropriate. Therefore, the following IR
`comments were sent to the Sponsor on October 06, 2015.
`
`FDA acknowledges receipt ofthe dissolution datafor the clinical and stability batches which
`wereprovided in thefile named "disstab.xpt" contained in section 3.2.P.8. 3. We have the
`following additional comments regarding this datafile:
`
`0
`
`It is noted that the data were onlyprovidedfor 3 specification-sampling timepoints (I, 2,
`and 5 hr). Provide the dissolution datafor thefollowing additional timepoints ifthey are
`available: 0. 5, 3, and 4 hr.
`
`Specifi) in which studies each clinical lot was used (e.g., which clinical trial?).
`0
`0 Submit the complete dissolution data, in ".xpt"format, for thefollowing clinical lots:
`N452626, N452627, and N452628 (0.5, I, 2, 3, 4 and 5 hr).
`
`In flleir response received on October 12, 2015, the Sponsor stated that the dissolution data at
`0.5, 3, and 4 hours were not available and thus not provided The Applicant also clarified the
`
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`

`QUALITY ASSESSMENT
`
`NDA 208082
`
`confusion caused by the bulk batch numbers and the packaging batch numbers. The data for the
`clinical batches have been previously provided and used for plots in Figure 38-8 above.
`
`Reviewer’s Assessment:
`
`proposed acceptance criteria are deemed acceptable.
`
`0 The proposed acceptance criteria include limits for three time points, and the ranges are
`within :l:10%. All the clinical and registration batches conform to the proposed
`acceptance criteria. However it appears that an alternative limit for the final time point
`(Q: (”‘4’ in 4 hr) may be applicable to provide tighter quality control.
`Based on the communications with the Applicant, the dissolution data for time points
`other than the proposed specification time points (0.5, 3, and 4-hr time point) were not
`provided. Therefore the acceptability of the alternative limit of“ = “9‘" in 4 hr”
`cannot be confirmed/ supported by the data.
`Considering the proposed limit for 5 hr shifted upwards to (we) (instead of M0), the
`
`38.5. Absence of Extended release Claim
`
`(m4)
`
`In the assessment oftheformulation ofyourproposedproduct, FDA has identified
`M0 ercipients;
`
`(5) (4)
`
`(b) (4)
`
`(hm)- However, _vou have neither claimed ER characteristics,
`nor included ER in the proposed name ofthe drug product. Please clarifir why an ER claim was
`not requestedfor your proposed drug product.
`
`In their response received on Dec 22, 2015, the Applicant confirmed that an ER claim will not be
`requested for this NDA. Per the definition in the United States Phannacopeia General Chapter
`<1151>, an “extended-release” product is one “that is deliberately modified to protract the
`release rate of the API compared to that observed for an immediate-release dosage form.”
`There is no other fonnulation of deutetrabenazine. The comparative BA studies submitted in the
`NDA compared the deutetrabenazine to the IR tablets of tetrabenazine, which is a different drug
`molecule. The results suggested that the differentiated PK profiles compared with the listed drug
`(Xenazine) were due to the selective deuterium placement in SD-809 instead of drug product
`formulations.
`
`In addition, the presence of the polyethylene oxide excipient in the SD-809 tablet formulation
`aids release of deutetrabenazine in the areas of the digestive tract where the drug is maximally
`soluble. However, this excipient’s role does not affect therapeutic efficacy of SD-809 in terms of
`frequency of dosing or the daily dose requirement.
`
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`
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`

`QUALITY ASSESSMENT
`
`NDA 208082
`
`Therefore, the Applicant does not intend to make extended-release claims for SD-809 and has
`not otherwise proposed labeling or naming for SD-809 that would indicate that the product
`should be identified as an extended-release dosage form.
`
`Reviewer’s Assessment:
`
`0 The NDA for SD-809 (deutetrabenazine