CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`209606Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`Recommendation: APPROVAL
`
`NDA 209606
`
`Review #1
`
`Dru Name/Dosa ' e Form
`
`nasidenib Mes late tablets
`
`Stren- h
`
`Oand 100m
`
`Route of Administration
`
`Rx/OTC Dispensed
`Applicant
`US agent, if applicable
`
`Celgene Corp.
`
`SUBMISSION(S)
`REVIEWED
`
`DOCUMENT
`DATE
`
`DISCIPLINE(S) AFFECTED
`
`_-_—_
`
`_-_—_
`
`_-_—_
`———_
`_-_—_
`_-_—_
`
`
`Nina Ni Anamitro Bane 'ee
`
`DISCIPLINE
`
`Drug Master File/Drug
`Substance
`
`Drug Product
`
`Microbiology
`Facili
`
`Bio oharmaceutics
`
`Regulatory Business
`Process Manager
`Application Technical Lead
`Environmental
`
`Quali Review Team
`PRIMARY REVIEWER SECONDARY REVIEWER
`
`Rohit Tiwali
`
`Benjamin Stevens
`
`Nina Ni
`
`David Anderson
`
`S
`
`Zhon. L1
`
`Banu Zolnik
`
`Rabiya Laiq
`
`Anamitro Banerjee
`Ying Zhang
`N
`n/
`
`Zhihao Peter 0 in
`
`O onanabofa Eradiri
`m
`
`n/
`
`Sherita McLamore
`
`S
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 1 of 2
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSMENT
`
`APPEARS THIS WAY ON ORIGINAL
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 2 of 2
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSNIENT
`
`Quality Review Data Sheet
`
`Date Review
`
`Com . 1eted
`
`1/26/ l 7
`
`No Review
`
`No Review
`
`No Review
`
`Adequate
`information
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`provided in the
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DNIFs:
`
`DMF(1:)(4
`
`Type
`
`Type IV
`
`Holder
`
`Item Refert.lnce((:)(4 Status
`
`Adequate
`
`Type III
`
`Type 1]]
`
`Type III
`
`Type 111
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`No Review
`
`Adequate
`information
`
`B. Other Documents: IND, RLD, or sister a
`
`lications
`
`
`
`2. CONSULTS
`
`N/A
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 1 of 1
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSMENT
`
`Executive Summary
`
`1.
`
`Recommendations and Conclusion on Approvability
`
`OPQ recommends APPROVAL of the NDA 209606 for IDHIFATM (enasidenib) tablets
`50 and 100 mg with the following Post-Approval Commitment:
`
`The applicant has committed to a Post Marketing Commitment (PMC) to4provide
`.
`.
`.
`.
`.
`(m )
`a revzsed control strategvfor mitigating nsks related to
`
`As part of this action, OPQ grants a (fig-month re-test period for the drug substance when
`stored
`(m4) and an 18-month drug product
`expiration period when stored at USP controlled room temperature conditions [i.e. 20°C -
`25°C (68°F - 77°F)] with excursions permitted between15°C — 30°C (59°F - 86°F).
`
`H.
`
`Summary of Quality Assessments
`
`A. Product Overview
`
`NDA 209606 was submitted as a 505(b)(1) NDA under the Federal Food, Drug and
`Cosmetic Act by the Celgene Corporation. The drug product, IDI-IIFATM (enasidenib)
`tablets, 50 and 100 mg, is a first-in—class, selective, targeted inhibitor of the mutant
`isocitrate dehydrogenase-2 (IDH2) enzyme indicated for the treatment of patients with
`relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. The
`active, enasidenib mesylate is a new molecular entity (NIVIE) which received orphan
`designation. Enasidenib mesylate was originally investigated under IND 117631.
`
`The dosing regimen for IDIHFATM (enasidenib) Tablets consists of 100 mg once daily
`until disease progression or until unacceptable toxicity. Dose adjustments for toxicities
`are outlined and include interruption of administration until toxicity resolves then
`resuming at 50 mg daily increasing to 100 mg daily if the patient continues to tolerate
`therapy.
`
`Based on the information provided in this application (original submission and in
`responses to information requests), OPQ considers all review issues adequately addressed
`and potential risks to patient safety, product efficacy, and product quality mitigated
`appropriately. Accordingly, OPQ recommends APPROVAL of NDA 209606 and grants
`a_ iii-month re-test period for the drug substance and an 18-month drug product expiration
`
`period when stored under controlled room temperature in the commercial packaging with
`the aforementioned PMC.
`
`
`Proposed Indication(s) including
`Intended Patient Population
`
`Treatment of patients with relapsed or refractory acute
`myeloid leukemia (ANIL) with an IDH2 mutation
`
`
` Duration of Treatment
`hronic (minimum of 6 months)
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 1 of 4
`
`Effective Date: 14 February 2017
`
`

`

`
`
`QUALITY ASSESSNIENT
`
`
`
`Maximum Daily Dose
`
`Alternative Methods of
`
`Administration
`
`B. Quality Assessment Overview
`Drug Substance
`The drug substance, enasidenib mesylate, is a white to ofl-white non-hygroscopic
`powder. The drug substance is an achiral molecule that exhibits polym01phic behavior.
`Multiple crystalline forms for the mesylate salt (15) and for the free base (1 1) were
`identified and characterized. Polymorph control was discussed prior to NDA
`submission (July 2016 Type B meeting) and during the review cycle (see Drug Product
`review pages 19-21). Ultimately it was concluded that
`M“) was the most
`(m4) form and was chosen for development.
`
`Enasidenib mesylate drug substance is a NIVIE that is synthesized by
`
`(Ina)
`
`fourteen potentially genotoxic impurities identified. Of the fomteen, thirteen were
`AMES negative and Derek inactive and one impurity was confirmed genotoxic (mu)
`). The use of
`mu) has the potential to form (mm
`which are genotoxic. The applicant addresses that concern by including
`specification and acceptance criteria for
`(mo in the drug product
`release specifications.
`
`There were
`
`(mm
`The drug substance is stored in
`. The applicant provided 12 months of long term and 6
`months accelerated stability data for the drug substance packaged in the
`aforementioned container closure system and proposed a 93 month re-test date for the
`drug substance. The stability data was acceptable and demonstrated no noteworthy
`trends. Accordingly, the proposed {ii—month re-test date for the drug substance stored
`at
`M“) in the proposed container closure can be granted.
`
`Drug Product
`The drug product, IDHIFATM (enasidenib) tablets, is presented as 50 and 100 mg
`yellow film coated tablets containing 60 and 120 mg of the drug substance (enasidenib
`mesylate), respectively. The 50 and 100 mg tablets are debossed with either “50” or
`“100” on one side and “ENA” on the other. The drug product composition includes:
`the active, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose acetate
`succinate, iron oxide yellow, magnesium stearate, microcrystalline cellulose,
`polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium starch glycolate,
`talc, and titanium dioxide. The 50 and 100 mg tablets are dose proportional and are
`manufactured from
`(m4) at a commercial batch
`size of :2; Kg. The {'4’} Kg batch size translates to
`M") of the 50 mg tablets and
`
`OPQ-XOPQ-TEM—0001v04
`
`Page 2 of 4
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSNIENT
`
`(m4) of the 100 mg tablets. The drug product will be packaged in 30—count, square,
`white HDPE bottles with a push down and turn
`(m4) closure, a liner and
`desiccant.
`
`Eighteen months of long term and 6 months of accelerated stability data were included
`for six commercial scale batches (3 batches of each strength) of the drug product
`manufactured at the proposed commercial manufacturing site and packaged in the
`proposed commercial container closure system. The data was acceptable and within
`the prescribed acceptance criteria with no notable trends or excursions. The proposed
`drug product specification together with the PMC and the controls for impurities in the
`drug substance are adequate to ensure that the critical quality attributes of this product
`are well controlled. The available stability data supports the proposed 18-month
`expiryfor the drug product when stored under USP controlled room temperature.
`
`Process
`
`(b) (4)
`
`Biopharmaceutics
`This application included data from the PK, bioavailability and food effect studies in
`healthy volunteers. Results of the aforementioned studies will be reviewed by the
`Office of Clinical Pharmacology (OCP). The Applicant conducted a Phase 1 PK study
`with the 50 and 100 mg strengths of enasidenib, therefore, no Biowaiver was
`requested.
`
`The proposed dissolution method for the drug product is USP Apparatus 2 (paddle) at
`75 rpm for Q= 33% in 30. This method is acceptable and the NDA is recommended for
`approval from the Biopharmaceutics perspective.
`
`OPQ-XOPQ-TEM—0001v04
`
`Page 3 of 4
`
`Effective Date: 14 Febluary 2017
`
`

`

`QUALITY ASSESSNIENT
`
`Facilities
`
`This NDA included the following seven sites :
`
`o
`
`(b) (4)
`
`Adequate descriptions were provided for all sites. Following a review of the
`application, inspectional documents, and pre-approval inspection results, there are no
`significant, outstanding manufacturing or facility risks that prevent the approval of this
`application. The Overall Manufacturing Inspection Recommendation is approval.
`
`Environmental Assessment
`
`Approval of this NDA will increase the use of the active moiety, enasidenib mesylate.
`However, the applicant included a claim for categorical exclusion from conducting an
`environmental impact statement (EIS) or environmental assessment (EA) under 21
`Code of Federal Regulations (CFR) Sections 25.31(b) on the basis that estimated
`concentration of the active moiety into the aquatic environment is less than 1 part per
`billion (ppb).
`
`The claim of categorical exclusion from an environmental assessment is valid since the
`estimated increase usage of the active moiety is well below the allowable EIC of 1 part
`per billion (ppb).
`
`The request for categorical exclusion is granted.
`
`C. Special Product Quality Labeling Recommendations (NDA only)
`n/a
`
`D. Final Risk Assessment
`
`Included drug product section of this IQA.
`
`OPQ-XOPQ-TEM—0001v04
`
`Page 4 of 4
`
`Effective Date: 14 February 2017
`
`

`

`Sherita
`McLamore
`
`Digitally signed by Sherita McLamore
`Date: 6/19/2017 03:11:23PM
`GUID: 503257950000415755492db5bb8b1a5c
`
`138 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`{For NDA Only}
`
`I. Package Insert
`
`1. Highlights of Prescribing Information
`
`IDHIFA™ (enasidenib) tablets, for oral use
`Initial U.S. Approval: 201X
`
`Tablets: 50 mg or 100 mg (3)
`
`Information Provided in NDA
`Item
`Product Title (Labeling Review Tool and 21 CFR 201.57(a)(2))
`Proprietary name and established
`Provided
`name
`Dosage form, route of
`administration
`Controlled drug substance symbol
`(if applicable)
`Dosage Forms and Strengths (Labeling Review Tool and 21 CFR
`201.57(a)(8))
`Summary of the dosage form and
`strength
`
`2. Section 2 Dosage and Administration
`
`Provided
`
`NA
`
`Provided
`
`Do not split or crush IDHIFA tablets. Administer IDHIFA tablets orally about the same
`time each day.
`
`Information Provided in NDA
`Item
`(Refer to Labeling Review Tool and 21 CFR 201.57(c)(12))
`Special instructions for product
`Provided
`preparation (e.g., reconstitution,
`mixing with food, diluting with
`compatible diluents)
`
`3. Section 3 Dosage Forms and Strengths
`
`IDHIFA is available in the following tablet strengths:
`
`
`
`
`
`50 mg tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed
`“ENA” on one side and “50” on the other side.
`100 mg tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed
`“ENA” on one side and “100” on the other side.
`
`

`

`_ Information Provided in NBA
`(Refer to Labeling Review Tool and 21 CFR 201.57(c)(4))
`Available dosa - e forms
`Provided
`
`Strengths: in metric system
`Provided
`Active moiety expression of
`Provided
`strength with equivalence statement
`
`(if applicable)
`A description of the identifying
`characteristics of the dosage forms,
`including shape, color, coating,
`scoring, and imprinting, when
`a. licable.
`
`
`
`
`
`Provided
`
`4. Section 11 Description
`
`IDHIFA (enasidenib) is an inhibitor of isocitrate dehydrogenase-2 (1DH2) enzyme.
`Enasidenib is available as the mesylate salt with the chemical name:
`2-methyl— 1 —[(4—[6-(trifluoromethyl)py1idin—2—yl]-6— {[2—(t1ifluoromethyl)pyridin—4—
`yl]amino} - 1 ,3 ,5—t1iazin-2—yl)amino]propan—2—ol methanesulfonate.
`
`Or
`
`2-Propanol, 2-methyl—1-[[4-[6-(t1ifluoromethyl)-2-pyridinyl]-6-[[2-(t1ifluoromethy1)-4-
`pyridinyl]amino-l ,3,5-triazin-2-yl]amino]-, methanesulfonate (l : l).
`
`The chemical structure is:
`
`/ I CF3
`CF3
`\ N
`N/
`N \N
`\ ' NAN/AN
`H
`H%H
`
`. CH3SO3H
`
`The empirical formula is C19H17F6N70 - CH3SO3H (C20H21F6N7O4S), and the molecular
`weight is 569.48 g/mol. Enasidenib is practically insoluble (solubility S74 mcg/mL) in
`aqueous solutions across physiological pH range (pH 1.2 and 7.4).
`
`IDHIFA (enasidenib) is available as a 50 mg tablet (equivalent to 60 mg enasidenib
`mesylate) and a 100 mg tablet (equivalent to 120 mg enasidenib mesylate) for oral
`administration. Each tablet contains inactive ingredients of colloidal silicon dioxide,
`hydroxypropyl cellulose, hypromellose acetate succinate, iron oxide yellow, magnesium
`stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl
`sulfate, sodium starch glycolate, talc, and titanium dioxide.
`
`

`

`Provided
`
`Provided
`
`Provided
`
`Information Provided in NDA
`Item
`(Refer to Labeling Review Tool and 21 CFR 201.57(c)(12), 21 CFR
`201.100(b)(5)(iii), 21 CFR 314.94(a)(9)(iii), and 21 CFR 314.94(a)(9)(iv))
`Proprietary name and established
`Provided
`name
`Dosage form and route of
`administration
`Active moiety expression of
`strength with equivalence statement
`(if applicable)
`For parenteral, otic, and ophthalmic
`dosage forms, include the quantities
`of all inactive ingredients [see 21
`CFR 201.100(b)(5)(iii), 21 CFR
`314.94(a)(9)(iii), and 21 CFR
`314.94(a)(9)(iv)], listed by USP/NF
`names (if any) in alphabetical order
`(USP <1091>)
`Statement of being sterile (if
`applicable)
`Pharmacological/ therapeutic class Provided
`Chemical name, structural formula,
`Provided
`molecular weight
`If radioactive, statement of
`important nuclear characteristics.
`Other important chemical or
`physical properties (such as pKa or
`pH)
`
`NA
`
`NA
`
`Provided
`
`5. Section 16 How Supplied/Storage and Handling
`16.1
`How Supplied
`
`50 mg tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed “ENA”
`on one side and “50” on the other side.
`
` Bottles of 30 with a desiccant canister (NDC 59572-705-30)
`
` revised to
`
`100 mg tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed
`“ENA” on one side and “100” on the other side.
`
` Bottles of 30 with a desiccant canister (NDC 59572-710-30)
`
` revised to
`
`16.2
`
`Storage
`
`(b) (4)
`
`(b) (4)
`
`

`

`Store at 20°C - 25°C (68°F - 77°F); excursions permitted between 15°C - 30°C (59°F
`- 86°F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed.
`Store in the original bottle (with a desiccant canister) to protect from moisture.
`(I!) (4)
`
`Manufactured for and marketed by:
`Celgene Corporation
`Summit, NJ 07901
`
`Licensed from:
`
`Agios Pharmaceuticals
`Cambridge, MA 02139
`
`Trademarks are the property of their respective owners.
`
`IDHIFATM is a trademark of Celgene Corporation.
`
`Pat. www.celgene.com/therapies
`
`© 2016—201X Celgene Corporation, All Rights Reserved.
`
`lDHPI.001/PPI.001 XX/l 7
`
`Information Provided in NBA
`
`(Refer to Labeling Review Tool and 21 CFR 201.57(c)(17))
`Stren h of dosa - e form
`
`Available units (e.g., bottles of 100 Provided
`
`tablets)
`Identification of dosage forms, e.g.,
`shape, color, coating, scoring,
`
`imprinting, NDC number
`Special handling (e.g., protect from Provided
`li-
`t
`
`
`
`
`
`
`
`
`Storage conditions
`Manufacturer/distributor name (21 Provided
`CFR 201.1
`5
`
`Reviewer’s Assessment of Package Insert: Adequate with comment.
`
`See assessment above.
`
`

`

`II. Labels:
`
`Container and Carton Labels
`
`Container Label:
`
`Carton Label:
`The product is not packaged in carton. So there is no carton label provided.
`
`(b) (4)
`
`

`

`Item
`
`Information provided in the
`container label
`Provided
`
`Information provided in the
`carton label(s)
`NA
`
`Provided
`
`NA
`
`Not required for oral tablets
`
`NA
`
`Provided
`
`Provided
`
`NA
`
`NA
`
`Not required for oral tablets
`
`NA
`
`Proprietary name,
`established name (font size
`and prominence (21 CFR
`201.10(g)(2))
`Dosage strength (21CFR
`201.10(d)(1); 21 CFR
`201.100(b)(4))
`Route of administration (21
`CFR 201.100(b)(3)), not
`required for oral
`Net contents* (21 CFR
`201.51(a))
`“Rx only” displayed
`prominently on the main
`panel (21 CFR
`201.100(b)(1)
`The list of inactive
`ingredients, 21CFR
`201.10(a), if not oral dosage
`form; and quantitative
`ingredient information, if
`parenteral injection. 21CFR
`201.100(b)(5)(iii)**, only
`required for carton label
`NDC number (21 CFR
`207.35(b)(3)(i))
`Lot number and expiration
`date (21 CFR 201.17)
`Storage conditions
`Bar code (21CFR
`201.25)***
`Sterility Information (if
`applicable)
`See packaging insert for
`dosage information (21 CFR
`201.55), only required for
`carton label
`Name of
`manufacturer/distributor
`Add “Swallow whole, do not
`And others, if space is
`chew or split tablets”
`available
`*21 CFR 201.51(h) A drug shall be exempt from compliance with the net quantity
`declaration required by this section if it is an ointment labeled ‘‘sample’’, ‘‘physician’s
`
`Provided, need to revise
`Provided
`
`Provided
`
`Provided
`
`NA
`
`Provided
`
`Provided
`
`NA
`
`NA
`
`NA
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`

`

`sample”, or a substantially similar statement and the contents of the package do not
`exceed 8 grams.
`**For solid oral dosage forms, CDER policy provides for exclusion of “oral” from the
`container label
`
`***Not required for Physician’s samples. The bar code requirement does not apply to
`prescription drugs sold by a manufacturer, repacker, relabeler, or private label distributor
`directly to patients, but versions of the same drug product that are sold to or used in
`hospitals are subject to the bar code requirements.
`
`Reviewer’s Assessment of Labels: Adequate with comment.
`
`The following comment on the container label needs to be conveyed to the applicant:
`
`0 The storage condition listed in the container needs to be revised to: Store at
`20°C - 25°C (68°F - 77°F); excursions permitted between 15°C - 30°C (59°F -
`86°F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed.
`
`List ofDeficiencies:
`
`The following comment needs to be conveyed to the applicant regarding the container label:
`
`0 The storage condition listed in the container needs to be revised to: Store at 20°C - 25°C
`
`(68°F - 77°F); excursions permitted between 15°C - 30°C (59°F - 86°F) [see USP
`
`Controlled Room Temperature]. Keep the bottle tightly closed.
`
`Overall Assessment and Recommendation: Approval pending on the update on the container
`label.
`
`See evaluation above.
`
`Primary Labeling Reviewer Name and Date: Nina Ni, Ph.D., 05/31/2017
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed): Anamitro
`
`Banerjee, Ph.D., May 31, 2017
`
`

`

`Nina
`Ni
`
`Anamitro
`Banerjee
`
`Digitally signed by Nina Ni
`Date: 5/31/2017 03:52:21PM
`GUID: 502d1ab500002afbbe642f8f37136920
`
`Digitally signed by Anamitro Banerjee
`Date: 5/31/2017 03:53:58PM
`GUID: 5075764700003844b7bc89632228509f
`
`39 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSM ENT
`
`BIOPHARMACEUTICS
`
`Product Background:
`
`NDA: 209606-0RIG-1
`
`Drug Product Name I Strength: ldhifa° (enasidenib) tablet, 50 mg and 100 mg
`
`Route of Administration: Oral
`
`Applicant Name: Celgene Corporation
`
`Review Summary:
`
`Enasidenib is a targeted inhibitor of the mutant isocitrate dehydrogenease-Z enzyme indicated
`
`for the treatment of patients with relapsed or refractory acute myeloid leukemia with an IDH2
`mutation.
`
`Enasidenib tablet is to be administrated orally once daily.
`
`The clinical development of the proposed drug product included 8 clinical studies. Four Phase 1-
`
`3 studies were conducted. The approval of the application is based on Study AGZZl—C—OOl.
`
`Three studies assessed the PK, bioavailability and food effect in healthy volunteers.
`
`The final regulatory dissolution method and acceptance criterion are shown below.
`
`
`
`900 mL Q = (“3% in 30 minutes
`0.6% $05 in 0.1 N HCL
`USP l| (paddle),
`75 rpm
`
`Discriminating power of the dissolution method was not demonstrated for critical process and
`
`manufacturing parameters.
`
`The Applicant conducted a Phase 1 PK study (AG-221-CP—001) with both proposed strengths of
`
`enasidenib (50 mg, 100 mg). Therefore, there is no need for a Biowaiver request. The afore-
`
`mentioned PK study is being evaluated by the OCP Reviewer.
`
`The clinical development program for the proposed product included mainly Formulation 2 and
`
`Formulation 3. The differences between the Formulation 2 and Formulation 3 are deemed
`
`OPQ—XOPQ—TEM-0001v03
`
`Page 1 of 14
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSM ENT
`
`minor by the Drug Product Reviewer.
`
`In addition, the Applicant used both formulations in the
`
`clinical safety and efficacy study. The comparative dissolution profiles between F2 formulation
`
`and F3 formulation for the 50 mg and 100 mg strengths, respectively, indicated that the minor
`
`formulation change did not impact dissolution.
`
`Some minor manufacturing changes i.e. debossing were implemented for the commercial to-
`
`be-marketed drug product. In support of this change, dissolution profile comparisons between
`
`Formulation 3 and the To-be-Marketed (TBM) drug product were submitted. Dissolution
`
`profiles between formulation 3 and the TBM drug product are overlapping indicating that
`
`debossing did not impact dissolution.
`
`RECOMMENDATION
`
`From the Biopharmaceutics perspective, NDA 209606 for ldhifao (enasidenib) tablet, 50 mg and
`
`100 mg is recommended for APPROVAL.
`
`APPEARS THIS WAY ON ORIGINAL
`
`0PQ—XOPQ—TEM-0001v03
`
`Page 2 of 14
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSM ENT
`
`Composition Information:
`
`Enasidenib tablets are prepared from
`
`W". Note that the Applicant is seeking
`
`approval for only 50 mg and 100 mg strengths (Table 1).
`
`Table 1. Composition of Enasidenib Tablets (Formulation 3)
`
`Strength (label claim)‘
`“5109
`a):
`Amount pe
`60
`120
`(b) (4)
`
`Component
`
`‘
`Rtgelraeliiie
`
`Function
`
`‘ Active
`Ingredient
`
`4
`(b)( ) c122?!
`
`“M"
`
`
`
`
`
`00-90007 mesylate drug
`Module 3.2.34.1 ‘
`substance
`Specifications
`
`Microcrystalline cellulose
`I
`NF/Ph. Eur.
`
`Hydroxypropyl cellulose
`|
`NFlPh. Eur.
`
`Sodium Iauryl sulfate
`I
`NFlPh. Eur.
`Sodium starch glycolate
`NFlPh. Eur.
`NF
`Hypromellose acetate succinate
`NFiPh. Eur.
`Colloidal silicone dioxide
`NFi’Ph. Eur,
`Magnesium stearate
`
`
`
`
`
`
`(b) (4)
`
`Total
`
`| 249.6 l 4992(b) (4)
`
`Reference: ELN 8353
`
`List Submissions being reviewed (table):
`
`Original dated 12/30/2016
`
`BCS Designation
`
`Reviewer’s Assessment:
`
`Solubility:
`
`Enasidenib has low aqueous solubility. The solubility data in aqueous media in the pH range of
`
`1.2-7.5 is shown in Table 2. The solubility in various biologically relevant media is shown in
`
`Table 3. The Applicant stated that enasidenib exhibits a high permeability across Caco-2 cells
`
`(17.9 X 10‘ cm/s). Therefore, it may be classified as a BCS Class II compound.
`
`Table 2. Solubility of enasidenib at various pH range
`
`.
`2
`
`0.1N HCI
`0.0m HCI
`
`pH
`(measured)
`1.25
`2.3
`
`Solubility
`(uglmL)
`74
`11
`
`
`
`3
`
`5
`3
`50 mM P04
`3
`4.5
`50 mM acetate
`4.6
`3
`
`6.8
`|
`50 mM P04
`6.8
`4
`|
`7.5
`|
`50 mM P04
`7.4
`|
`Reference: ELN 8353
`
`
`0PQ—XOPQ—TEM-0001v03
`
`Page 3 of 14
`
`Effective Date: 18 Feb 2016
`
`

`

`Effective Date: 18 Feb 2016
`
`m S
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 4 of 14
`
`imulated Gastic Fluid (SGF)
`Fasted Stated Simulated
`
`Intestinal Fluid (FaSSlF)
`Fed State Simulated Intestinal
`
`Fluid (FeSSIF)
`Reference: ELN 8353
`
`

`

`QUALITY ASSESSMENT
`
`Dissolution Method and Acceptance Criteria
`
`USP
`
`Acceptance Criteria
`
`0.6% SDS in 0.1 N HCL
`
`900 mL Q ='% in 30 minutes
`
`Apparatus/RPM
`USP || (paddle),
`
`75 rpm
`
`
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 5 of 14
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`Figure 4. 56 66-00007 Released at Various Paddle Speeds
`
`Effective Date: 18 Feb 2016
`
`
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 7 of 14
`
`

`

`QUALITY ASSESSMENT
`
`
`
`
`
`Effective Date: 18 Feb 2016
`
`
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 8 of 14
`
`

`

`QUALITY ASSESSM ENT
`
`2) Effect of API particle size on Dissolution
`
`Three different API particle size ranges were used in the manufacture of the tablets which were
`
`subjected to dissolution testing (Table 5). Dissolution profiles of tablets with micronized, target,
`
`and large API are shown in Figure 7.
`
`Table 6. Enasidenib tablets manufactured with different API particle size
`Table 11. (26-90007 API Particle Sizes Tested
`
`
`‘
`
`
`
`Dv(10)(um)
`
`
`
`‘ Dv(50)(um)
`
`‘
`
`
`
`Dv (90)(um)
`
`‘
`
`"’“"
`
`
`
`
`AP'Type
`L°t
`.
`.
`150029-
`Mlcromzed
`.
`.
`
`micronized
`
`150029
`
`404-14-05-75
`Reference: ELN 8353
`
`
`
`
`
`Effect of API Size For 100 mg Tablets
`
` Reference: ELN 8353
`
`100
`
`30
`
`60
`
`40
`
`20
`
`
`
`9‘(090007Released
`
`
`
`
`
`+ Typical API
`+Lalse API
`+Miuumzed API
`
`
`
`O
`
`15
`
`30
`
`45
`
`b0
`
`75
`
`90
`
`Time (min)
`
`Figure 7. The effect of particle size on dissolution of 100 mg enasidenib tablets
`
`It was found that tablets with larger API particle size exhibited faster dissolution than tablets
`
`with smaller particle size. This is an unusual phenomenon since tablets with micronized API are
`
`expected to exhibit faster dissolution due to increased surface area. The Applicant asserts that
`
`(am) differences between the tablets contributed to this behavior; however this
`
`rationaleis not fully supported by the data. It is this Reviewer's opinion that the dissolution
`
`method is not discriminatory for changes in API particle size, and the particle size range should
`
`be included in the specifications. During the review cycle, the Drug Product Reviewer sent IR
`
`comments to the Applicant regarding the need for an API particle size specification; an upper
`
`090 limit of (um um was set for the API (for further details refer to the Drug Product Review).
`
`0PQ-XOPQ—TEM-0001v03
`
`Page 10 of 14
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`3) Effect of
`Dissolution
`
`M“) Content on
`
`Tablets were prepared with high l (b)(4)%)’ target ( 8%) and low ( (b)(4)%)
`(b) (4)
`
`mm
`
`content. Dissolution profiles of tablets prepared with
`
`are shown in Figure 8. It
`
`appears that dissolution is not discriminatory for variations in
`(m4)
`
`(m4)
`
`(”M
`
`content. Similar to levels of the
`
`the changes in the
`
`content did not impact
`
`dissolution (data not shown).
`
`(I!) (4)
`
`Figure 7. The effect of
`
`mm on dissolution of 100 mg enasidenib tablets
`
`In conclusion, the dissolution method is discriminating for changes in
`(0)“) levels that are greater
`than a} % relative to the target formulation. The method is not discriminating for
`M“)
`, API particle size,
`(m4) and
`(mu)
`
`levels. Overall, the dissolution method is not discriminating for critical process and manufacturing
`
`parameters.
`
`Dissolution method acceptance criteria
`
`Reviewer's Assessment:
`
`The Applicant’s proposed acceptance criteria of Q: {23% in 30 min is acceptable.
`
`0PQ-XOPQ—TEM-0001v03
`
`Page 11 of 14
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSM ENT
`
`Bridging of Formulations
`
`Reviewer’s Assessment:
`
`The clinical development program for the proposed product included mainly Formulation 2 and
`
`Formulation 3 (refer to the schematic overview below. The Applicant conducted Study AGZZ-C—
`
`001, a Phase 1/2 dose escalation study, with all the formulations (Formulation 1a, Formulation
`
`1b, Formulation 2 and Formulation 3). Parts 1 and 2 expansion phases of Study AGZZl-C-001,
`
`which is the basis for approval, were conducted with Formulation 2 and Formulation 3. The
`
`Applicant conducted the food effect study (A6221-C-002) with Formulation 2 and the single
`
`dose PK (A6221-CP-001) and ADME-BA(A6221-CP-002) studies with Formulation 3. The
`
`differences between Formulation 2 and Formulation 3 are deemed minor by the Drug Product
`
`Reviewer. The PK studies are being evaluated by the OCP Reviewer. The comparative
`
`dissolution profiles between F2 formulation and F3 formulation for 50 mg and 100 mg tablets
`
`are shown in Figures 8 a-b. The similarity values between the F2 vs F3 formulations for 50 mg
`
`and 100 mg strengths are 56 and 82, respectively, indicating that the minor formulation change
`
`did not impact dissolution.
`
`Some minor manufacturing changes i.e. debossing were implemented for Formulation 3, and
`
`for the commercial to-be-marketed drug product. In support of this change, dissolution profile
`
`comparisons between Formulation 3 and the To-be—Marketed (TBM) drug product were
`
`submitted (Figure 9 a-b). Dissolution profiles between Formulation 3 and the TBM drug
`
`product are overlapping indicating that debossing did not impact dissolution.
`
`APPEARS THIS WAY ON ORIGINAL
`
`0PQ—XOPQ—TEM-0001v03
`
`Page 12 of 14
`
`Effective Date: 18 Feb 2016
`
`

`

`mmmtmmm
`
`QUALITY ASSESSMENT
`
`kmmnmtw—m
`
`Minor determined
`
`with 9:42 Elem
`
`
`
`Formulation la
`5 mg. 10 mg
`
`Formulation lb
`50 mg, 200 mg
`
`Formulation 2
`50 mg, 100 mg
`
`Uncoated
`
`Uncoated
`
`Uncoated
`
`Fomma‘ion 3
`50 mg’ '00 mg’ 150
`mg, 200 mg
`Coated
`
`To-be Marketed
`(debossed)
`
`AG221-C—001: Phase 1:"2 Pivotal Clinical Study—Dose escalation phase
`
`AG221—C-001: Phase 1/2 Pivotal Study-Part
`land 2 expansion phase
`
`AGZZl-C-OOZ:
`SD food effect
`
`1 Formulation 2 is used
`i Formulation 3. is used
`Blue box: PK studies
`
`
`
`Green box: Phase 1—3
`
`www~fda-9°"
`
`t
`
`AGZZl-AML-004:
`
`Phase 3 ongoing
`
`
`
`AGZZl—AML—OOS:
`
`Phase 1b/2 ongoing
`
`AGZZl-CP-UUI: SD PK
`
`AGZZl-CP-OOZ:
`
`ADME/BA
`
`
`
`
`
`
`
`
`
`
`
`t
`lCK]
`90 ‘
`80 A
`70 ‘
`
`3 5° ‘
`3 so
`g 40 t
`
`j: ,
`10 t
`0 ‘
`0
`
`
`
`Comparative dlssolutlon profiles In QC media between F2 and F3
`iormulltlon,100 mg
`
`+r3 100 mg (batch chc)
`
`...H mm m mm
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Tlme (mln)
`
`Comparative dlssolutlon profiles in QC media between F2 and F3
`formulatlon, 50 mg
`
`
`
`“:0
`90
`80
`70
`
`6"
`‘g’
`3 50
`3 40
`
`j:
`10
`0
`
`~
`
`0
`
`+F 3 5° "'8 "mt" WSW)
`
`+;;;§Sgtggaatw
`
`v
`80
`
`100
`
`20
`
`4O
`
`60
`
`Time (min)
`
`
`
`Figure 8. Comparative dissolution profiles between F2 vs. F3 formulation in QC media (a)Left panel-50
`
`mg, (b) Right panel-100 mg (Plotted by the Reviewer)
`
`APPEARS THIS WAY ON ORIGINAL
`
`OPQ-XOPQ—TEM-0001v03
`
`Page 13 of 14
`
`Comparatlve dlssolutlon profiles In QC media between F3 formulation and Tn-Be-
`
`Mum-daw- 100 m:
`
`-0-l'3100mg(balthTCCCl
`
`+F3 ToBe-MalkaieMWNW)
`
`100
`
`88
`
`8
`
`xDissolved S
`
`40
`30
`20
`10
`
`
`
`

`

`QUALITY ASSESSM ENT
`
`Comparative dissolution profiles In QC media between F3 formulationvs To-
`Be-Marketed Batch, 50 mg
`
`—o—i A '30 mg (Haul! lLBW)
`-l—H In no Markmnrl [Vi/NV)
`
`1 (l)
`90
`80
`70 -
`i)"
`50
`
`AI)
`w
`A)
`10
`
`9‘Dissolved
`
`1(1)
`80
`60
`40
`£0
`0
`Time (min)
`
`Figure 9. Comparative dissolution profiles between F3 formulation vs. To-Be-Marketed Formulation
`
`in QC media (3) Left panel-50 mg, (b) Right panel—100 mg (Plotted by the Reviewer)
`
`Biowaiver Request
`
`Reviewer’s Assessment:
`
`The Applicant conducted Phase 1 PK study (AG-221-CP-001) with 50 mg, 100 mg strengths.
`
`Therefore, there is no need for a Biowaiver request. This study is being evaluated by OCP
`reviewer.
`
`RECOMMENDATION
`
`From the Biopharmaceutics perspective, NDA 209606 for ldhifa° (enasidenib) tablet, 50 mg and
`
`100 mg is recommended for APPROVAL.
`
`Primary Biopharmaceutics Reviewer Name and Date:
`
`6/1/2017
`
`Banu S. Zolnik, PhD
`
`Secondary Reviewer Name and Date
`
`6/1/2017
`
`Okpo Eradiri, PhD
`
`OPQ—XOPQ—TEM-0001v03
`
`Page 14 of 14
`
`Effective Date: 18 Feb 2016
`
`

`

`Banu
`Zolnik
`
`Digitally signed by Banu Zolnik
`Date: 6/01/2017 10:14:19AM
`GUID: 508da7270002a568e175a2c0dd90f334
`
`Okponanabofa
`Eradiri
`
`Digitally signed by Okponanabofa Eradiri
`Date: 6/01/2017 11:27:15AM
`GUID: 50bdfe8d00003559ede66be3fd299f65
`
`

`

`ALITY ASSESSMENT
`
`ATTACI-HVIENT I: Final Risk Assessments
`
`A. Final Risk Assessment — NDA 209606 (IDHIFA“l tablets), Celgene Corporation
`
`a) Drug Product
`
`From Initial Risk Identification
`
`Review Assessment
`
`Faftm that
`can impact the
`CQA
`
`Initial Risk
`Rankin
`
`g
`
`B's".
`Mitigation
`A r
`. roach
`
`Final Risk
`Evaluation
`
`Lifecy‘l?
`Cons1derations/
`Comments
`
`Assay, Stability
`
`Physic-I stability
`(solid state)
`
`Content
`Uniformity
`
`Microbial Limits
`
`Dissolution -
`BCS Class I a.
`III
`
`. Formulation
`- Container closure
`0 Process parameters
`- Scale/equipments
`- Site
`
`- Formulation
`- Container closure
`
`° Raw materials
`' ”05°55 parameters
`- Scale/equipments
`- Site
`
`- Formulation
`
`- Container closure
`' Raw mate'ials
`: gmflfigfigs
`- Site
`
`- Formulation
`
`- Container closure
`: ProclI' gitggraiifneters
`- Scale/equipments
`. Site
`
`° Formulation
`' comm” C_'°5"‘e
`- Raw materials
`- Process parameters
`- Scale/equipments
`- Site
`
`Assessed during
`DWdOpment
`and controlled
`via specs
`
`Assessed during
`Development and
`controlled via
`Specs-
`
`Assessed during
`Development and
`controlled via
`Specs
`
`Assessed during
`Development and
`controlled Via
`SPCCS
`
`Assessed during
`Development and
`controlled via
`
`Specs
`
`Controls are in place
`
`Acceptable
`
`Controls are in place.
`
`Acceptable
`
`PMC to provide a revised
`control stragtegy for
`mitigating risks related to
`(b) (4)
`
`Acceptable
`
`Controls are in place.
`
`Acceptable
`
`Controls are in place
`
`Acceptable
`
`

`

`Sherita
`McLamore
`
`Digitally signed by Sherita McLamore
`Date: 6/19/2017 03:20:43PM
`GUID: 503257950000415755492db5bb8b1a