CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`211192Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`
`QUALITY ASSESSMENT
`
`
`Recommendation: APPROVAL
`
`
`
`NDA 211192
`Review #1
`
`
`TIBSOVO (ivosidenib) tablets, 250 mg
`250 mg
`Oral
`Rx
`Agios Pharmaceuticals
`n/a
`
`
`DOCUMENT
`DATE
`21-Dec-17
`30-Jan-18
`22-Mar-18
`30-Mar-18
`01-May-18
`10-May-18
`
`DISCIPLINE(S) AFFECTED
`
`All
`DP
`DS
` DP
`DS
`DP
`
`Quality Review Team
`PRIMARY REVIEWER
`Rohit Tiwari
`
`SECONDARY REVIEWER
`Charles Jewel
`
`Amit Mitra
`Ying Zhang
`n/a
`Ying Zhang
`Joan Zhao
`Rabiya Laiq
`
`Sherita McLamore
`n/a
`Amit Mitra
`
`Anamitro Banerjee
`Rakhi Shah
` n/a
`Zhihao Peter Qiu
`Banu Zolnik
`n/a
`
`n/a
`n/a
`Anamitro Banerjee
`
`Drug Name/Dosage Form
`Strength
`Route of Administration
`Rx/OTC Dispensed
`Applicant
`US agent, if applicable
`
`
`SUBMISSION(S)
`REVIEWED
`Original Submission
`Amendment (SD 0006)
`Amendment (SD 0014)
`Amendment (SD 0017)
`Amendment (SD 0023)
`Amendment (SD 0025)
`
`
`
`DISCIPLINE
`Drug Master File/Drug
`Substance
`Drug Product
`Process
`Microbiology
`Facility
`Biopharmaceutics
`Regulatory Business
`Process Manager
`Application Technical Lead
`Laboratory (OTR)
`Environmental
`
`
`
`
`OPQ-XOPQ-TEM-0001v04 Page 1 of 1 Effective Date: 14 February 2017
`
`
`

`

`Holder
`
`Item Referenced
`
`Status
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`Type
`III
`
`
`Type
`III
`
`
`Type
`III
`
`
`Type
`III
`
`
`Type
`III
`
`
`Type
`III
`
`
`Date Review
`Completed
`No Review
`
`No Review
`
`No Review
`
`No Review
`
`No Review
`
`No Review
`
`Comments
`Adequate
`information
`provided in the
`NDA
`Adequate
`information
`provided in the
`NDA
`Adequate
`information
`provided in the
`NDA
`Adequate
`information
`provided in the
`NDA
`Adequate
`information
`provided in the
`NDA
`Adequate
`information
`provided in the
`NDA
`
`DESCRIPTION
`Ivosidenib development
`
`
`QUALITY ASSESSMENT
`
`Quality Review Data Sheet
`
`
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`DMF
`Type
`#
`
`
`
`B. Other Documents: IND, RLD, or sister applications
`DOCUMENT
`APPLICATION NUMBER
`119341
`
`IND
`
`
`2. CONSULTS
`N/A
`
`
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`

`
`QUALITY ASSESSMENT
`
`
`Executive Summary
`
`
`
`I. Recommendations and Conclusion on Approvability
`
`
`
`
`OPQ recommends APPROVAL of NDA 211192 for TIBSOVO (ivosidenib) tablets, 250
`mg. As part of this action, OPQ grants a
`month re-test period for the drug substance
`and a 24-month drug product expiration period when
`stored at stored at “20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to
`30°C (59°F to 86°F) [see USP controlled room temperature]. There are no outstanding
`issues and no post-approval quality agreements to be conveyed to the applicant.
`
`
`II.
`
`Summary of Quality Assessments
`
`
`A. Product Overview
`NDA 211192 was submitted for TIBSOVO (ivosidenib) tablets, 250 mg in accordance
`with section 505(b)(1) of the Food, Drug and Cosmetic Act. Ivosidenib is a once daily,
`orally bioavailable, small-molecule, isocitrate dehydrogenase-1 inhibitor indicated for the
`treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia
`(AML) with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-
`approved test. Ivosidenib is an NME which was originally investigated under IND
`119341 and was granted orphan designation for the treatment of AML.
`
`
`Ivosidenib is a small chiral molecule with two stereogenic centers. It is manufactured
` As the drug substance is a BCS Class 2
`
`
`compound with low aqueous solubility,
`
` The drug product, TIBSOVO (ivosidenib) tablets,
`250 mg, is presented as a 250-mg, immediate-release solid oral dosage form containing
`the
` micro-crystalline cellulose, croscarmellose sodium, sodium lauryl
`sulfate, colloidal silicon dioxide, and magnesium stearate. It is a blue, oval tablet
`debossed with “IVO” on one side and “250” on the other.
`
`The recommended dosing regimen for TIBSOVO (ivosidenib) tablets is 500 mg orally
`once daily until disease progression or unacceptable toxicity.
`
`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 211192 and grants
`a
`month re-test period for the drug substance and a 24-month expiration period for the
`drug product when stored at USP controlled room temperature in the proposed
`commercial packaging.
`
`
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`
`
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`
`
`Proposed Indication(s) including
`Intended Patient Population
`
`QUALITY ASSESSMENT
`
`
`Indicated for the treatment of adult patients with
`
`relapsed or refractory acute myeloid leukemia (AML)
`
`with an isocitrate dehydrogenase-1 (IDH1) mutation as
`
`detected by an FDA-approved test.
`Until disease progression or unacceptable toxicity
`
`Duration of Treatment
`
`Maximum Daily Dose
`
`Alternative Methods of
`Administration
`
`500 mg
`
`None
`
`
`B. Quality Assessment Overview
`Drug Substance
`Ivosidenib is a small chiral molecule with two stereogenic centers. It is a white to
`light yellow, non-hygroscopic crystalline solid that is practically insoluble in aqueous
`solutions across a physiological relevant pH range
`
` Ivosidenib has excellent
`permeability across Caco-2 cells and has therefore been classified as a BCS Class 2
`compound.
`
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`

`
`
`QUALITY ASSESSMENT
`
`
`
`Ivosidenib Tablets:
`The drug product, TIBSOVO (ivosidenib) tablets, 250 mg, is presented as a 250-mg,
`immediate-release solid oral dosage form containing the
` microcrystal-
`line cellulose, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide,
`and magnesium stearate.
`
`
`The drug product is a blue, oval tablet debossed with “IVO” on one side and “250” on
`the other. The drug product formulation contains no novel excipient. All excipients
`are compendial and commonly used in solid oral dosage forms and demonstrate good
`compatibility with the drug substance.
`
`The QTPP was defined and the CQAs were identified. CQAs for the drug product
`include description, identification, assay, degradation products, uniformity of dosage
`units,
` solid form and dissolution.
`
` at a commercial batch size
`The drug product is manufactured by
` tablets. The drug product is packaged in 90 and
` Kg which corresponds to
`175 cc square, HDPE bottles (14 and 60 count, respectively) with a 1.0 gram
`
`desiccant canister and a 38 mm
`closure with an induction seal.
`
`The drug product specifications are consistent with ICH Q6A and are based on batch
`analyses as well as stability data. Of note the acceptance criterion for
` was NMT
`%. This limit was proposed based on batch analyses and stability data. Results
`from the open dish study
`
`
`%. Accordingly the proposed %
`acceptance criteria was adequately justified. The originally proposed drug product
`specification did not include tests or acceptance criteria for microbial limits or
`elemental impurities. In the January 30, 2018 amendment the applicant provided a
`
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`
`
`QUALITY ASSESSMENT
`
`
`risk-based assessment of potential sources of elemental impurities. This assessment
`
`was based on ICH Q3D. The results demonstrated that the total elemental impurity
`
`level from all sources in the drug product is expected to be consistently less than %
`
`of the permitted daily exposure (PDE). Accordingly, no additional controls are
`
`required. The microbial attributes of the drug product were tested on stability for up to
`18 months and no significant trends were observed. Additionally, the drug product was
` The results of
` were well below the
`
`accepted limit of
` The drug product specifications provide adequate controls to ensure the
`quality of the drug product throughout the product expiry.
`
`The proposed specification and acceptance criteria for the drug product, together with
`controls for impurities in the drug substance are adequate to ensure that the critical
`quality attributes of this product are well controlled.
`
`In support of the proposed 24 month expiry, the applicant provided up to 12 months of
`stability data for three pilot scale batches of the drug product (batches WNSB, WNSC
`and WNSD). The batches were manufactured according to the commercial process and
`packaged in 90-cc 14 count and 175-cc 60-count HDPE bottles. The samples were
`stored under the long-term (30°C/65% RH) and accelerated (40°C/75% RH)
`conditions. The samples were stored in the 60- and 14-count bottles. The samples in
`the 60-count bottles were film-coated and debossed. The samples in the 14-count
`bottles were film- coated and non-debossed. Additional supportive studies were
`performed
` for up to 12 months) and in an open dish to
`help assess the impact of temperature and humidity on the relevant critical quality
`attributes of the drug product
`
`
`The applicant also completed a bulk hold study, photostability, and forced degradation
`studies for the drug product. The stability studies were executed in accordance with
`the ICH 1A and Q1B. No significant changes were observed in description, assay, or
`degradation products under any storage condition.
`
`
`
`
`The available stability data shows consistency over time and support the proposed
`expiry. Based on the 12 months of stability data included in this application, Agios
`proposed and the FDA accepts the expiration dating period of 24 months for the drug
`product when stored at stored at controlled room temperature 20°C to 25°C (68°F to
`77°F);excursions permitted between 15°C to 30°C (59°F to 86°F).
`
`The application is recommended for approval from a drug product perspective.
`
`Process
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`
`
`QUALITY ASSESSMENT
`
`
`
`
`
`Biopharmaceutics
`The acceptability of the proposed dissolution method and acceptance criterion for the
`routine QC testing of the proposed drug product at batch release and on stability was
`assessed. The dissolution method included a USP Apparatus II (Paddle) at 50 rpm in
`900 mL of 50mM phosphate buffer, pH 6.8 with 0.6% SDS. The proposed dissolution
`acceptance criterion is Q= % in 30 minute. The applicant used in vitro comparative
`dissolution profiles to bridge the clinical and commercial drug product. The calculated
`f2 values ranged from 63 to 81 which demonstrate that the dissolution profiles are
`similar.
`
`Both the proposed dissolution method and acceptance criterion were deemed
`acceptable for batch release and stability testing. The f2 values were sufficiently
`similar to substantiate the bridge; therefore, the bridging between the clinical batches
`(non-debossed) and the proposed commercial drug product (debossed) is acceptable. This
`application is recommended for approval from a biopharmaceutics perspective.
`
`
`Facilities
`There were 7 facilities included in this application:
`
`
`DRUG SUBSTANCE:
`Drug substance, Ivosidenib, is manufactured by
` This site was responsible for drug substance manufacture,
`
`
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`
`
`QUALITY ASSESSMENT
`
`
`packaging and quality control testing. Based on the initial risk assessment, this site
`
`was considered high risk by virtue of the drug substance being designated as a new
`
`molecule entity (NME), high potent drug with orphan drug designation. The
`manufacturing process
` The site was last inspected
`
` with profile code
`on
` covered. Accordingly a
`PAI was not requested and the site was recommended for approval for the
`aforementioned operations based on the information provided in the submission and
`satisfactory compliance history.
`
`
` is responsible for elemental impurity testing for the
`drug substance. This site was most recently tested in
` The inspection did not
`issue any 483 observations and CTL profile is acceptable. Since there is no application
`specific concern identified, this site is considered acceptable for to perform the
`aforementioned operations based on the information provided in the submission and
`satisfactory compliance history.
`
`
` is responsible for testing of primary stability
` and Ivosidenib
`batches of ivosidenib drug substance,
`Tablets, 250 mg, stability testing of annual commitment batches of ivosidenib drug
`substance,
` and Ivosidenib Tablets, 250 mg, and Quality
`control testing of Ivosidenib Tablets, 250 mg
` Based on the initial risk
`assessment, this site was considered to have a medium risk. This facility was last
`inspected in
` for a PAI only and no 483 was issued. Based on the inspection
`history, this site was recommended for approval for the aforementioned operations
`based on the information provided in the submission and satisfactory compliance
`history.
`
`
`Drug product, TIBSOVO (ivosidenib) tablets, is manufactured, quality control, release
`and stability tested by
`
`
`
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`

`QUALITY ASSESSMENT
`
`
` was included in this NDA as the site to preform
`
`primary packaging for the drug product. The drug product is packaged into white
`
`
` desiccant. The bottles are closed with
`HDPE bottles with
`
` closure with an induction heat seal liner. The facility was last inspected
`
` with the focus on PAI of a combination product. The facility is considered
`in
`acceptable and is recommended for approval based on the inspection history.
`
`
` was included in this
`NDA as the site to preform secondary packaging for the drug product. No additional
`evaluation will be performed.
`
`Environmental Assessment
`The approval of this application will increase the use of Ivosidenib; however, the
`estimated concentration of the substance at the point of entry into the aquatic
`environment is
` ppb (
` ppb). The applicant provided a claim for
`categorical exclusion and a statement of no extraordinary circumstances under 21 Code
`of Federal Regulations (CFR) Sections 25.31(b). The categorical exclusion cited is
`appropriate based on the estimated amount of drug to be produced for direct use. The
`claim of categorical exclusion is therefore acceptable and should be granted.
`
`
`C. Special Product Quality Labeling Recommendations (NDA only)
`n/a
`
`
`
`
`D. Final Risk Assessment (see Attachment)
`Appended at the end of the drug product review.
`
`
`
`
`
`
`
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`

`Sherita
`McLamore
`
`Digitally signed by Sherita McLamore
`Date: 5/31/2018 01:05:45PM
`GUID: 503257950000415755492db5bb8b1a5c
`
`89 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
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`

`

`Item
`
`Information
`Provided in NDA
`Product title, Drug name (201.57(a)(2))
`Proprietary name
`Proprietary:
`and established
`Tibsovo
`name
`Established Name:
`ivosidenib tablets
`tablets, oral
`
`Reviewer’s Assessment
`
` Satisfactory
`
`Satisfactory
`
`
`
`
`R
`
`QUALITY ASSESSMENT
`
`
`LABELING
`
`
`{For NDA only}
`
`
`Regional Information (NDA
`
`)
`
`
`
`1.14 Labeling
`
`1. Package Insert: Is being conducted with the labeling review. ***
` (a) “Highlights” Section (21CFR 201.57(a))
`
`
`
`Dosage form,
`route of
`administration
`Controlled drug
`substance symbol
`(if applicable)
`Dosage Forms and Strengths (201.57(a)(8))
`A concise
`Tablets: 250 mg
` Satisfactory
`summary of
`dosage forms and
`strengths
`Reviewer’s Assessment: The highlight is satisfactory with respect to proprietary and
`established name, dosage form and strengths.
`
`N/A
`
`N/A
`
`
`
`OPQ-XOPQ-TEM-0001v03
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`Page 1 of 8
`
`Effective Date: 18 Feb 2016
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`(b) (4)
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`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Strengths: in metric
`system
`A description of the
`identifying characteristics
`of the dosage forms,
`including shape, color,
`coating, scoring, and
`imprinting, when
`applicable.
`Reviewer’s Assessment: This section may be modified according to PLR, if needed.
`
`
`Blue oval-shaped film-coated
`tablet debossed “IVO” on one
`side and “250” on the other
`side.
`
` Satisfactory
`
`#11: Description (21CFR 201.57(c)(12))
`
`TIBSOVO (ivosidenib) is an inhibitor of isocitrate dehydrogenase-1 (IDH1) enzyme. The
`chemical name is (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)-amino]-2-
`oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-
`carboxamide. The chemical structure is:
`
`
`F
`
`N
`
`O
`
`N
`
`O
`
`N
`
`CN
`
`
`
`N
`
`O
`
`NH
`
`Cl
`
`F
`
`F
`
`
`
`
`
`
`
`
`The molecular formula is C28H22ClF3N6O3 and the molecular weight is 583.0 g/mol.
`Ivosidenib is practically insoluble in aqueous solutions between pH 1.2 and 7.4.
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 2 of 8
`
`Effective Date: 18 Feb 2016
`
`QUALITY ASSESSMENT
`
`Item
`Available dosage forms
`
`
`(b) “Full Prescribing Information” Section
`# 3: Dosage Forms and Strengths (21CFR 201.57(c)(4))
`
`
`Information Provided in NDA Reviewer’s Assessment
`
`Tablets
`Satisfactory
`
`250 mg
`
`
`
`Satisfactory
`
`

`

`QUALITY ASSESSMENT
`
`
`
`TIBSOVO (ivosidenib) is available as a film-coated 250 mg tablet for oral administration.
`
`Each tablet contains the following inactive ingredients:
` colloidal silicon dioxide,
`croscarmellose sodium, hypromellose acetate succinate, magnesium stearate,
`
`microcrystalline cellulose, and sodium lauryl sulfate. The tablet coating includes FD&C
`blue #2, hypromellose, lactose monohydrate, titanium dioxide, and triacetin.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`OPQ-XOPQ-TEM-0001v03
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`Page 3 of 8
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`Effective Date: 18 Feb 2016
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`(4)
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`
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`
`QUALITY ASSESSMENT
`
`Item
`
`Proprietary name and
`established name
`
`Dosage form and route of
`administration
`Active moiety expression of
`strength with equivalence
`statement for salt (if
`applicable)
`Inactive ingredient
`information (quantitative, if
`injectables
`21CFR201.100(b)(5)(iii)),
`listed by USP/NF names.
`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, solubility, or pH)
`
`
`Information Provided in
`NDA
`
`Proprietary name: TIBSOVO
`Established name:
`
`ivosidenib tablets
`Tablets, Oral
`
` “TIBSOVO (ivosidenib) is
`
`available as a film-coated
`250 mg tablet ---“.
`
`Reviewer’s
`Assessment
`Satisfactory
`
`Satisfactory
`
` Satisfactory
`
`See the text above under
`description section
`
`Satisfactory for oral
`dosage form
`
`N/A
`
`inhibitor of isocitrate
`dehydrogenase-1 (IDH1)
`enzyme
`Yes
`
`N/A
`
`Yes
`
`N/A
`
`Satisfactory
`
`Satisfactory
`
`N/A
`
`Satisfactory
`
`Reviewer’s Assessment: The applicant could not determine the pKa. Since the drug is
`practically insoluble within physiological pH, there is no need to provide pH of solution
`information. The minor edits (highlighted in yellow and strikeouts) of the “Description
`Section” was included in the PI.
`
`#16: How Supplied/Storage and Handling (21CFR 201.57(c)(17))
`
`
`250 mg tablet: Blue oval-shaped film-coated tablet debossed “IVO” on one side and
`“250” on the other side.
`
`• 60-count bottles of 250 mg tablets with a desiccant canister (NDC 71334-100-01)
`
`OPQ-XOPQ-TEM-0001v03
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`Page 4 of 8
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`Effective Date: 18 Feb 2016
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`
`QUALITY ASSESSMENT
`
`Handling and Disposal
`
`
`
`
`Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to
`30°C (59°F to 86°F) [see USP Controlled Room Temperature].
`
`
`Reviewer’s Assessment: It was decided in the labeling meeting that no special handling
`
`of this oncology drug is needed.
`
`
`
`
`Information Provided in NDA Reviewer’s Assessment
`Item
`Strength of dosage form 250 mg tablets
`Satisfactory
`Available units (e.g.,
` 60 tablets
`Satisfactory
`bottles of 100 tablets)
`Identification of dosage
`forms, e.g., shape, color,
`coating, scoring,
`imprinting, NDC number
`Special handling (e.g.,
`protect from light, do
`not freeze)
`Storage conditions
`
`Satisfactory
`
` Satisfactory
`
`Satisfactory
`
`250 mg tablet: Blue oval-
`shaped film-coated tablet
`debossed “IVO” on one side
`and “250” on the other side.
`None
`
` Store at 20°C to 25°C (68°F to
`77°F); excursions permitted
`between 15°C to 30°C (59°F to
`86°F) [see USP Controlled
`Room Temperature].
`
`
`
`
`
`
`
`Item
`
`Manufacturer/distributor
`name (21 CFR 201.1)
`
`Manufacturer/distributor name listed at the end of PI, following Section #17
`
`Information Provided in
`NDA
`Manufactured for and
`marketed by:
`Agios Pharmaceuticals, Inc.
`Cambridge, MA 02139
`
`Reviewer’s Assessment
`
`Satisfactory
`
`
`
`
`
`
`
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 5 of 8
`
`Effective Date: 18 Feb 2016
`
`

`

`
`
`
`
`
`Immediate Container Label
`
`
`
`250 mg tablets
`
`
`
`
`
`QUALITY ASSESSMENT
`
`
`
`
`
`
`
`
`
`
`
`
`Reviewer’s Assessment:
`The applicant provided the following required items: Established name, dose strength,
`prescription only, lot #, bar code, and expiration date. DMEPA may have additional
`comments.
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 6 of 8
`
`Effective Date: 18 Feb 2016
`
`(b) (4)
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`Item
`
`Proprietary name,
`established name (font
`size and prominence
`(21 CFR 201.10(g)(2))
`Strength (21CFR
`201.10(d)(1); 21.CFR
`201.100(b)(4))
`
`
`Comments on the Information Provided in
`NDA
`
` Proprietary name: Tibsovo
`Established name: ivosidenib tablets
`
`
`Conclusions
`
` Satisfactory
`
`
`Correct strength was included.
`
`
` Satisfactory
`
`
`
`60 tablets
`
` None
`
`None
`
`None
`
`None
`
`None
`
`None
`
`Satisfactory
`
`Satisfactory
`
`Satisfactory
`
`Satisfactory
`
`Satisfactory
`
`Satisfactory
`
`Satisfactory
`
`Satisfactory
`
`Net contents (21 CFR
`201.51(a))
`Lot number per 21 CFR
`201.18
`Expiration date per 21
`CFR 201.17
`“Rx only” statement per
`21 CFR 201.100(b)(1)
`Storage
`(not required)
`NDC number
`(per 21 CFR 201.2)
`(requested, but not
`required for all labels or
`labeling), also see 21 CFR
`207.35(b)(3)
`Bar Code per 21 CFR
`201.25(c)(2)**
`Name of
`None
`manufacturer/distributor
`
`Others
`
`*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 sample’’, or a substantially similar
`statement and the contents of the package do not exceed 8 grams.
`**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: Satisfactory
`
`Carton Labeling: None included.
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 7 of 8
`
`Effective Date: 18 Feb 2016
`
`

`

`
`
`
`
`Reviewer’s Assessment:
`
`
`
`List of Deficiencies: None
`
`
`
`
`
`QUALITY ASSESSMENT
`
`
`
`
`
`
`
`
`
`
`
`
`Primary Labeling Reviewer Name and Date:
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 8 of 8
`
`Effective Date: 18 Feb 2016
`
`

`

`Amit
`Mitra
`
`Anamitro
`Banerjee
`
`Digitally signed by Amit Mitra
`Date: 5/22/2018 02:54:17PM
`GUID: 502d1ab500002af97e86c5f6f3951edc
`
`Digitally signed by Anamitro Banerjee
`Date: 5/22/2018 03:11:09PM
`GUID: 5075764700003844b7bc89632228509f
`
`29 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`
`QUALITY ASSESSMENT
`
`
`BIOPHARMACEUTICS
`
`
`
`
`Product Background:
`
`NDA/ANDA: 211192-ORIG-1 [505(b)(1)]
`
`
`Drug Product Name / Strength: TIBSOVO (ivosidenib) tablets, 250 mg
`
`Route of Administration: Oral
`
`Applicant Name: Agios Pharmaceuticals Inc. (Agios)
`
`Review Summary:
`is
`tablets 250 mg, an isocitrate dehydrogenase-1 inhibitor,
`TIBSOVO (ivosidenib)
`proposed for the treatment of adult patients with relapsed or refractory acute myelo id
`leukemia (AML) with an IDH1 mutation as detected by an FDA-approved test.
`
`The Biopharmaceutics review is focused on the evaluation of the adequacy of the overall
`information/data supporting the proposed dissolution method and acceptance criterion,
`as well as formulation bridging in the drug product development.
`
`In Vitro Dissolution Method and Acceptance Criterion:
`The Applicant’s proposed dissolution method was reviewed in IND 119341, in which a
` SDS %) was recommended1. In the current submission, the Applicant
`provided an additional data to justify the amount of surfactant in the proposed dissolut io n
`medium. Based on the provided data, the following dissolution method and acceptance
`criterion are acceptable for release and stability:
`
`
`USP
`Apparatus
`
`Rotation
`Speed
`
`Medium
`
`Volume
`
`Cumulative % of Drug
`Dissolved
`(Label Claim)
`
`USP II
`(Paddle)
`
`50 RPM
`
`50 mM Phosphate Buffer pH
`6.8 with 0.6% SDS
`
`900 mL
`
`Q % in 30 minutes
`
`
`Formulation Bridging:
`The Applicant provided adequate dissolution data to support the bridging between the
`clinical batches (non-debossed) and the proposed commercial drug product (debossed).
`
`RECOMMENDATION:
`Based on the review of the overall information, from a Biopharmaceutics perspective,
`NDA 211192 for TIBSOVO (ivosidenib)
`tablets, 250 mg, is recommended for
`APPROVAL.
`
`
`
`
`
`
`
`1 DARRTS: IND 119341 REV-QUA LBIOPHARM-21 (Primary Review), final date 09/15/2017
`
`OPQ-XOPQ-TEM-0001v04 Page 1 of 8 Effective Date: 14 February 2017
`
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`
`
`SIGNATURES
`
`
`
`Primary Biopharmaceutics Reviewer Name and Date:
`
`
`Zhuojun Zhao, PhD
`Division of Biopharmaceutics
`Office of New Drug Products, OPQ
`
`Secondary Biopharmaceutics Reviewer Name and Date:
`
`Banu Zolnik, PhD
`Division of Biopharmaceutics
`Office of New Drug Products, OPQ
`
`
`
`
`
`
`05/22/2018
`
`
`
`5/29/2018
`
`OPQ-XOPQ-TEM-0001v04 Page 2 of 8 Effective Date: 14 February 2017
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`BIOPHARMACEUTICS ASSESSMENT
`
`List of Submissions being reviewed:
`
`
`
`Submissions Reviewed Document Date
`Original Submission
`12/21/2017
`
`
`
`
`I. Background:
`The Applicant’s dissolution method development report was reviewed in IND 119341 1.
`The proposed dissolution conditions, including the apparatus, rotation speed and volume
`of the dissolution medium, were found acceptable. However, additional data were
`requested in Type B CMC Teleconference Meeting dated September 18, 20172 to justify
`the amount of surfactant used in the proposed dissolution medium (50 mM Phosphate
`buffer, pH 6.8 containing 0.6% SDS).
`
`II. Current Submission
`a. Dissolution Method
`
`
`2 DARRTS: IND 119341 COR-MEET-03 (Meeting Minutes), final date 10/2/2017
`
`OPQ-XOPQ-TEM-0001v04 Page 3 of 8 Effective Date: 14 February 2017
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`
`Reviewer’s Comment:
`Based on the provided information, the proposed dissolution method medium, i.e. 50 mM
`Phosphate Buffer, pH 6.8 containing 0.6% SDS is adequately justified. Therefore, the
`proposed dissolution method is acceptable for the QC dissolution testing of the proposed
`drug product.
`
`The proposed dissolution method could discriminate variation in
`
`
`
`
`
`
`b. Dissolution Acceptance Criterion:
`The Applicant proposed a dissolution acceptance criterion of Q= % in 30 minutes based
`on dissolution profile data from the primary registration and supporting stability batches
`and release data for representative clinical batches4.
`Figure 2. Pooled Release and Stability Results for Ivosidenib Tablets, 250 mg
`
`
`4 \\cdsesub1\evsprod\nda211192\0001\m3\32-body-data\32r-reg-info\32r4-dissol-data\dissol-res.pdf
`
`
`
`OPQ-XOPQ-TEM-0001v04 Page 4 of 8 Effective Date: 14 February 2017
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`
`
`Figure 3. Individual Dissolution Results for Release and Stability (t=30 minutes)
`
`Reviewer’s Comment:
`The proposed dissolution acceptance criterion is acceptable.
`
`
`
`
`c. Bridging of Formulations:
`Two tablet presentations have been used during clinical development: (1) uncoated tablets
`(50, 200, and 250 mg) and (2) film-coated blue non-debossed tablets (250 mg). The
`difference between the film-coated clinical presentation and the proposed commercia l
`product is the addition of a debossed product identifier. The overview of tablet presentation
`used in each clinical studies is shown in Appendix 1. The composition of the Ivosidenib
`Tablets, 50 mg, 200 mg, and 250 mg used in clinical studies is shown below:
`Table 1: Composition of Ivosidenib Tablets, 50 mg, 200 mg, and 250 mg
`
`OPQ-XOPQ-TEM-0001v04 Page 5 of 8 Effective Date: 14 February 2017
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`The proposed commercial product, Ivosidenib Tablets, 250 mg is the same color and
`
`composition as the film-coated Ivosidenib Tablets, 250 mg in Table 1. The only differe nce
`
`between the clinical product and the proposed commercial product is the addition of a
`
`debossed product identifier. The intended commercial product is an oval, blue, film-coated
`
`tablet, debossed with “IVO” on one side of the tablet and “250” on the opposite side.
`
`The Applicant provided dissolution data and f2 values to support the comparabilit y
`between the non-debossed clinical tablets (uncoated (lot: TTZS) and film-coated (WDGF))
`and debossed film-coated registration batch (Lot: WNPY). The registration batches
`(primary stability batches) were manufactured using production scale equipment according
`to the commercial process at the commercial site.
`Table 2: Summary of Comparative Dissolution Results
`
`1Used in clinical studies AG120-C-001 and AG120-C-002
`Figure 4. Dissolution Profiles for Ivosidenib Tablets, 250 mg: Film-Coated, Non-
`debossed (Clinical Lot TTZV5) Versus Commercial Presentation Film-Coated,
`Debossed (Lot WNPY)
`
`
`
`
`
`
`5 Used in clinical study AG120-C-004 (food effect) and AG120-C-007 (clinical DDI study with itraconazole)
`
`OPQ-XOPQ-TEM-0001v04 Page 6 of 8 Effective Date: 14 February 2017
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`Figure 5. Comparative Dissolution Profiles for Ivosidenib Tablets , 250 mg
`
`(Uncoated, Non-debossed; Lot WDGF) Versus Commercial Presentation (Ivosidenib
`
`Tablets, 250 mg, Film-Coated, Debossed; Lot WNPY)
`
`
`
`
`
`As shown above, the addition of debossing does not have any detectable impact on the drug
`product’s dissolution profiles. Therefore, the dissolution data support the bridge between the
`clinical batches and the commercial presentation.
`
`d. Biowaiver Request:
`The Applicant
`is seeking approval for only one dosage strength (250 mg) and thus
`biowaiver request is not applicable for the application.
`
`Regional Information
`
`
`
` R
`
`Comparability Protocols: N/A
`
`Lifecycle Management Considerations: N/A
`
`OPQ-XOPQ-TEM-0001v04 Page 7 of 8 Effective Date: 14 February 2017
`
`

`

`
`QUALITY ASSESSMENT
`
`
`APPENDIX I: Overview of Tablet Presentation Used in Clinical Studies
`
`
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v04 Page 8 of 8 Effective Date: 14 February 2017
`
`
`

`

`Zhuojun
`Zhao
`
`Banu
`Zolnik
`
`Digitally signed by Zhuojun Zhao
`Date: 5/29/2018 12:39:04PM
`GUID: 508da6fd000284770cf4eecbae0