CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`210563Orig1s000
`210563Orig2s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`
`Recommendation: APPROVAL
`
`
`
`
`QUALITY ASSESSMENT
`
`
`
`
`
`
`
`
`NDA 210563
`Review #1
`
`
`Imbruvica® (Ibrutinib) Tablets
`140 mg, 280 mg, 420
`Oral
`Rx
`Pharmacyclics LLC
`N/A
`
`
`DOCUMENT
`DATE
`31-Aug-17
`21-Sept-17
`20-Oct-17
`3-Nov-17
`8-Dec-17
`18-Dec-17
`19-Dec-17
`
`DISCIPLINE(S) AFFECTED
`
`All
`DP
`DP, Biopharm
`DP
`Process
`Process
`DP
`
`Quality Review Team
`PRIMARY REVIEWER
`Sherita McLamore
`
`SECONDARY REVIEWER
`n/a
`
`Xing Wang
`Quamrul Majumder
`n/a
`Ziyang Su
` Om Anand
`Rabiya Laiq
`
`Sherita McLamore
`Xing Wang
`
`Anamitro Banerjee
`Ying Zhang
`n/a
`Ruth Moore
`Okponanabofa Eradiri
`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 (SD 1)
`Amendment (SD 2)
`Amendment (SD 4)
`Amendment (SD 5)
`Amendment (SD 8)
`Amendment (SD 9)
`Amendment (SD 11)
`
`
`
`DISCIPLINE
`Drug Master File/Drug
`Substance
`Drug Product
`Process
`Microbiology
`Facility
`Biopharmaceutics
`Regulatory Business
`Process Manager
`Application Technical Lead
`Environmental
`
`
`
`OPQ-XOPQ-TEM-0001v04 Page 1 of 1 Effective Date: 14 February 2017
`
`
`

`

`
`QUALITY ASSESSMENT
`
`
`Quality Review Data Sheet
`
`
`
`
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`
`A. DMFs:
`DMF #
`Type
`
`Holder
`
`Item Referenced Status Date Review
`Completed
`N/A
`No Review
`
`N/A
`
`No Review
`
`Type III
`
`
`Type III
`
`
`Comments
`Adequate
`information
`provided in
`the NDA
`Adequate
`information
`provided in
`the NDA
`
`
`
`B. Other Documents: IND, RLD, or sister applications
`DOCUMENT
`APPLICATION NUMBER
`205552
`
`NDA
`
`102688
`
`
`IND
`
`
`
`
`2. CONSULTS
`N/A
`
`
`
`DESCRIPTION
`Manufacture and control of
`Drug Substance
` Drug development
`
`
`OPQ-XOPQ-TEM-0001v04 Page 1 of 1 Effective Date: 14 February 2017
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`QUALITY ASSESSMENT
`
`
`Executive Summary
`
`
`
`I. Recommendations and Conclusion on Approvability
`
`
`
`
`The Office of Pharmaceutical Quality (OPQ) recommends APPROVAL of NDA 210563
`for IMBRUVICA® (ibrutinib) Tablets, 140 mg, 280 mg, 420 mg, 560 mg. As part of this
`action, OPQ grants a 24-month expiration period for the drug product when stored at
`stored at controlled room temperature 20°C to 25°C (68°F to 77°F) with excursions
`permitted between 15°C and 30°C (between 59°F and 86°F). The Office of
`Pharmaceutical Quality has no Post-Marketing Commitments (PMCs) or Post-Marketing
`Requirements (PMRCs) to be conveyed to the applicant.
`
`
`
`II.
`
`Summary of Quality Assessments
`
`
`A. Product Overview
`NDA 210563 was submitted for IMBRUVICA® (ibrutinib) Tablets, 140 mg, 280 mg, 420
`mg, 560 mg in accordance with section 505(b)(1) of the Food, Drug and Cosmetic Act.
`Ibrutinib is an orally bioavailable, small molecule, Bruton tyrosine kinase inhibitor (BTK).
`Imbruvica (Ibrutinib) originally investigated under IND 102,688 and approved under
`NDA 205552 (November 2013) as a 140 mg capsule for a variety of B-cell malignancies
`including:
` Mantle cell lymphoma (MCL) who have received at least one prior therapy
` Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
` CLL/SLL with 17p deletion
` Waldenström’s macroglobulinemia (WM)
` Marginal zone lymphoma (MZL) who require systemic therapy and have
`received at least one prior anti-CD20-based therapy
` Chronic graft versus host disease (cGVHD) after failure of one or more lines of
`systemic therapy
`
`
`The drug product, IMBRUVICA® (ibrutinib) tablets for oral use was designed to be a
`new, smaller tablet formulation of the approved product which offers a single tablet
`alternative to patients and reduces pill burden. Ibrutinib was granted breakthrough
`designation in 2013 and has orphan designation.
`
`The ibrutinib drug substance used in the manufacture of IMBRUVICA® (ibrutinib)
`Tablets, 140 mg, 280 mg, 420 mg, and 560 mg is identical to that which is used for the
`approved 140 mg ibrutinib capsules. The drug substance is a non-hygroscopic, small,
`chiral molecule that is manufactured
`. The
`applicant references NDA 205552 for all aspects of manufacture and control of the drug
`substance. The drug product is presented as a 140 mg, 280 mg, 420 mg, and 560 mg
`immediate release, film-coated tablets containing the active together with compendial,
`commonly used excipients. All four strengths are
`
`
`
`OPQ-XOPQ-TEM-0001v04 Page 1 of 6 Effective Date: 14 February 2017
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
` similar. They are easily differentiated by size, debossing, shape
`
`and/or color.
`
`
`
`The recommended dosing regimen of IMBRUVICA® Tablets for MCL and MZL is 560
`
`mg orally once daily until disease progression or unacceptable toxicity. The recommended
`dosing regimen for IMBRUVICA® Tablets for CLL/SLL and WM is 420 mg orally once
`daily until disease progression or unacceptable toxicity. The recommended dosing
`regimen for IMBRUVICA® Tablets for CLL/SLL when used in combination with
`bendamustine and rituximab (administered every 28 days for up to 6 cycles) is 420 mg
`orally once daily until disease progression or unacceptable toxicity. The recommended
`dosing regimen of IMBRUVICA for cGVHD is 420 mg orally once daily until cGVHD
`progression, recurrence of an underlying malignancy, 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 210563 and grants a
`24-month expiration period for the drug product when stored at ICH controlled room
`temperature in the commercial packaging.
`
`
`
`Proposed Indication(s) including
`Intended Patient Population
`
`
`
`Duration of Treatment
`
`Maximum Daily Dose
`
`Alternative Methods of
`Administration
`
` Mantle cell lymphoma (MCL) who have received
`at least one prior therapy
` Chronic lymphocytic leukemia (CLL)/Small
`lymphocytic lymphoma (SLL)
` CLL/SLL with 17p deletion
` Waldenström’s macroglobulinemia (WM)
` Marginal zone lymphoma (MZL) who require
`systemic therapy and have received at least one
`prior anti-CD20-based therapy
` Chronic graft versus host disease (cGVHD) after
`failure of one or more lines of systemic therapy
`Until disease progression or unacceptable toxicity
`
`MDD is 420 mg for CLL/SLL, WM and cGVHD and 560
`mg for MCL and MZL
`None
`
`
`B. Quality Assessment Overview
`Drug Substance
`Ibrutinib drug substance is a white to off-white, non-hygroscopic, highly-crystalline
`solid that is practically insoluble in water and is freely soluble in DMF, THF, DCM
`and DMSO. Ibrutinib drug substance is small chiral molecule that is manufactured
`
`
`
`
` The applicant references NDA 205552 for all aspects of manufacture and
`control of ibrutinib drug substance. NDA 205552 was submitted to the agency in April
`
`OPQ-XOPQ-TEM-0001v04 Page 2 of 6 Effective Date: 14 February 2017
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`
`
`QUALITY ASSESSMENT
`
`
`of 2013 and approved in November of that same year. The application is
`
`recommended for approval from the drug substance perspective.
`
`
`
`Drug Product
`
`The drug product is presented as 140 mg, 280 mg, 420 mg, and 560 mg film-coated,
`immediate release tablets. All four strengths are manufactured
`and are differentiated by color, shape, size, and debossing. The 140 mg tablet is
`presented as a
` round yellow-green tablet debossed on one side with “ibr” and
`“140” on the other side. The 280 mg tablet is presented as a
` oblong,
`purple tablet debossed on one side with “ibr” and “280” on the other side. . The 420
`mg tablet is presented as a
` oblong yellow-green to green tablet debossed
`on one side with “ibr” and “420” on the other side. The 560 mg tablet is presented as a
`oblong yellow to orange tablet debossed on one side with “ibr” and
`“560” on the other side. The tablet core formulation includes USP/NF grade lactose
`monohydrate, croscarmellose sodium, sodium lauryl sulfate, microcrystalline cellulose,
`colloidal silicon dioxide and magnesium stearate.
`
`
`
`
` The drug product formulation contains no novel excipient. All excipients
`are compendial and commonly used in solid oral dosage forms.
`
`The drug product is manufactured controlled, packaged, and release tested by Catalent
`CTS, LLC or by AbbVIe Inc at a commercial batch size of
` tablet which
`corresponds to
`for the 140, 280, 420 and 560 mg tablets,
`respectively. IMBRUVICA® (ibrutinib) Tablets, 140 mg, 280 mg, 420 mg, 560 mg
`will be packaged in
` blisters with push-through aluminum lidding foil. The
`secondary packaging for the blister cards is a
`carton. The blister
`packaging was chosen based on the ability to provide adequate protection for the drug
`product from moisture and light throughout its shelf life.
`
`The drug product specifications are consistent with ICH Q6A and 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 12 months of
`primary stability data for ten registration batches of the drug product: 3 batches each of
`560 mg, 420 mg and 140 mg strength and 1 batch of 280 mg strength. All batches used
`in the primary stability study were manufactured with the commercial formulation, at
`scale using the proposed commercial process and were manufactured at proposed
`commercial sites. All batches were packaged in the proposed commercial container
`closure systems. The stability protocol included a bracket (i.e. one batch of the 280 mg
`table). As all potencies were manufactured from
` the bracket was in
`accordance with ICH Q1D and therefore acceptable. In addition to the primary
`stability data, the applicant provided supportive stability data for clinical tablet batches
`(see drug product review for details of supportive data).
`
`OPQ-XOPQ-TEM-0001v04 Page 3 of 6 Effective Date: 14 February 2017
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`
`
`The stability studies were executed in accordance with the ICH 1A and Q1B. The
`
`available stability data shows consistency over time and the statistical analysis of the
`
`long term data support the proposed expiry. Based on the 12 months of stability data
`
`included in this application, Pharmacyclics, LLC. proposed and the FDA accepts the
`expiration dating period of 24 months for the drug product when stored between 20°C
`and 25ºC (with excursions permitted from between 15°C to 30ºC).
`
`The application is recommended for approval from the drug product perspective.
`
`Process
`The drug product is manufactured, packaged and release tested by AbbVie Inc. of IL
`and Catalent CTS, LLC of MO commercial batch size of
` tablet which
`corresponds to
` for the 140, 280, 420 and 560 mg tablets,
`respectively. The drug product is manufactured
`
`
`
`
` controls were described in sufficient
`The proposed process parameters and
`detail and justified. The applicant demonstrated the suitability of the manufacturing
`process for the drug product at commercial scale. The description of the manufacturing
`process includes appropriate
` controls and operating parameters. The
`application is recommended for approval from a manufacturing process perspective.
`
`Biopharmaceutics
`Ibrutinib is a BCS Class II drug. The biopharmaceutics review of this application
`focused on the acceptability of the proposed dissolution method and acceptance
`criterion for the routine quality control (QC) testing of the proposed drug product at
`batch release and on stability; the biowaiver request for the intermediate strengths (280
`and 420) and the bridging between the proposed commercial product and the product
`used in the clinical studies.
`
`The dissolution method for the 140 and 280 mg strengths included a USP Apparatus II
`(Paddle) at 75 rpm in 900 mL of 3.0% w/v Tween 20 in 0.05 M potassium phosphate
`buffer, pH 6.8@37.0± 0.5° C. The dissolution method for the 420 and 560 mg
`strengths included a USP Apparatus II (Paddle) at 75 rpm in 900 mL of 6.0% w/v
`Tween 20 in 0.05 M potassium phosphate buffer, pH 6.8@37.0± 0.5° C. It was
`concluded that the proposed in-vitro dissolution test is adequate for quality control as
`applicant has adequately studied the discriminating ability of the proposed dissolution
`method. Thus the dissolution methods and acceptance criterion of Q % at 45 min
`for all four strengths is acceptable.
`
`
`OPQ-XOPQ-TEM-0001v04 Page 4 of 6 Effective Date: 14 February 2017
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`With regards to the biowaiver and the bridging, it was concluded that the applicant
`
`provided adequate data to support the biowaiver request for intermediate strengths (280
`
`mg and 420 mg) and that the and that the bridging between the proposed commercial
`
`product and the product used in the clinical studies is acceptable. Accordingly, the
`
`biowaiver request was granted and this application is recommended for approval from
`a biopharmaceuticals perspective.
`
`Facilities:
`NDA 210563 included a total of ten (10) sites:
`
` AbbVie Inc. (FEI 3009751352): This site was responsible for the manufacture,
`packaging and labeling of final drug product. This site had a high initial risk
`assessment and a final recommendation of acceptable.
`
`
`OPQ-XOPQ-TEM-0001v04 Page 5 of 6 Effective Date: 14 February 2017
`
`(b) (4)
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
` Catalent CTS, LLC (FEI 3002929455): This site was responsible for the
`
`manufacture, release and stability testing of final drug product and release and
`
`stability testing of the drug substance. This site had a low initial risk
`
`assessment and a final recommendation of acceptable.
`
` AbbVie Inc. (FEI 1411365): This site was responsible for release and stability
`testing of final drug product. This site had a low to medium initial risk
`assessment and a final recommendation of acceptable.
`
`Following a review of this application and inspectional documents, it was concluded
`that there were no manufacturing risks that preclude approval of this application.
`Based on the firm’s inspectional history, EIR reviews and District Office (DO)
`recommendations, each of the manufacturing facilities included in NDA 210563 are
`acceptable and the Overall Manufacturing Inspection Recommendation for this NDA is
`approval.
`
`Environmental Assessment
`The applicant requested a categorical exclusion from the requirement for an
`environmental assessment under 21 CFR 25.15(d) and 21 CFR 25.31(b) based on the
`calculation of the expected introduction concentration (EIC) value for ibrutinib into the
`aquatic environment. The EIC was determined to be 0.225 ppb.
`
`The request for categorical exclusion is granted.
`
`
`C. Special Product Quality Labeling Recommendations (NDA only)
`n/a
`
`
`
`
`D. Final Risk Assessment (see Attachment)
`
`
`
`
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v04 Page 6 of 6 Effective Date: 14 February 2017
`
`

`

`Sherita
`McLamore
`
`Digitally signed by Sherita McLamore
`Date: 2/08/2018 10:21:10AM
`GUID: 503257950000415755492db5bb8b1a5c
`
`33 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`ENVIRONMENTAL ANALYSIS
`
`Imbruvica® (ibrutinib) capsules 140 mg has been commercially available in the United
`States since November 2013 (NDA 205552). Pharmacyclics was granted a categorical
`exclusion (under 21 CFR 25.31(b)) from the preparation of an environmental assessment
`of ibrutinib based on estimated concentration of less than 1 part per billion (ppb) of drug
`substance entering the aquatic environment at the point of entry (EIC-Aquatic).
`
`Pharmacyclics has developed a new tablet dosage form in four different strengths (140
`mg, 280 mg, 420 mg, and 560 mg). The new tablet dosage form is intended to be
`marketed for use in the same approved indications and at the same recommended dose
`level as the currently approved ibrutinib capsules. Therefore, no change is anticipated in
`the estimated quantity of the drug substance to be produced for direct use in any of the
`next five years. The quantity of drug substance to be used in all dosage forms and
`strengths will remain the same as presented in Section 1.12.14 Environmental Analysis of
`the approved NDA 205552. Justification for the categorical exclusion from environmental
`assessment of ibrutinib was presented in NDA 205552 and is applicable to the current
`submission as well. A cross-reference to the Section 1.12.14 Environmental Analysis of
`the approved NDA 205552 is provided.
`
`Reviewer’s Assessment: Adequate
`Per NDA 205552, for ibrutinib, EIC-Aquatic = 0.225 ppb < 1 ppb. The EA statement is
`adequate.
`
`
`
`Primary EA Reviewer Name and Date: Xing Wang, Ph.D., ONDP/DNDPI/NDPBII
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`Anamitro Banerjee, Ph.D., Acting Branch Chief, ONDP/DNDPI/NDPBII
`
`

`

`Xing
`Wang
`
`Anamitro
`Banerjee
`
`Digitally signed by Xing Wang
`Date: 1/04/2018 09:08:04PM
`GUID: 525daca300039122a4daaad45e49c6fb
`
`Digitally signed by Anamitro Banerjee
`Date: 1/04/2018 10:54:16PM
`GUID: 5075764700003844b7bc89632228509f
`
`

`

`QUALITY ASSESSMENT
`
`CHAPTER IV: Labeling
`
`Package Insert
`(a) “Highlights” Section (21CFR 201.57(a))
`
`Item
`
`Information
`Provided in NDA
`Product title, Drug name (201.57(a)(2))
`Proprietary name and
`IMBRUVICA®
`established name
`(ibrutinib)
`Dosage form, route
`Capsules, for oral use
`of administration
`Tablets, for oral use
`Controlled drug
`substance symbol (if
`applicable)
`Dosage Forms and Strengths (201.57(a)(8))
`A concise summary
`Capsule: 140 mg
`of dosage forms and
`Tablet: 140 mg, 280
`strengths
`mg, 420 mg and 560
`mg
`
`N/A
`
`Reviewer’s Assessment
`
`Adequate
`
`Adequate
`
`N/A
`
`Adequate
`
`Conclusion: Adequate
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
` (b) “Full Prescribing Information” Section
`
`# 3: Dosage Forms and Strengths (21CFR 201.57(c)(4))
`
`140 mg capsules
`
`Tablets: 140 mg, 280 mg, 420 mg, and 560 mg
`
`Information Provided in NDA
`Capsule, tablet
`See above
`Provided
`
`Reviewer’s Assessment
`Adequate
`Adequate
`
`Adequate
`
`Item
`Available dosage forms
`Strengths: in metric system
`A description of the identifying
`characteristics of the dosage
`forms, including shape, color,
`coating, scoring, and
`imprinting, when applicable.
`
`Conclusion: Adequate
`
`#11: Description (21CFR 201.57(c)(12))
`
`Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). It is a white to off-white solid with the
`empirical formula C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in
`dimethyl sulfoxide, soluble in methanol and practically insoluble in water. The chemical name for
`ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1-
`piperidinyl]-2-propen-1-one and has the following structure:
`
`IMBRUVICA (ibrutinib) is available as immediate-release oral capsules and immediate-release
`oral tablets.
`
`IMBRUVICA (ibrutinib) capsules for oral administration are
` contains the following
` Each capsule
`inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose,
`sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink.
`
`
`
`
`
`IMBRUVICA (ibrutinib) tablets for oral administration are available in the following dosage
`strengths: 140 mg, 280 mg, 420 mg, and 560 mg. Each tablet contains ibrutinib (active
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`QUALITY ASSESSMENT
`
`ingredient) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose
`sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and
`sodium lauryl sulfate. The film coating for each tablet contains ferrosoferric oxide (140 mg, 280
`mg, and 420 mg tablets), polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg and 560
`mg tablets), talc, titanium dioxide, and yellow iron oxide (140 mg, 420 mg, and 560 mg tablets).
`
`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)
`
`Conclusion: Adequate
`
`Information Provided in NDA
`IMBRUVICA (ibrutinib)
`
`Reviewer’s Assessment
`Adequate
`
`Capsule, tablets
`
`Free base, not salt
`
`Provided
`
`Ibrutinib is an inhibitor of
`Bruton’s tyrosine kinase (BTK)
`Provided
`
`Provided
`
`Adequate
`
`Adequate
`
`Adequate
`
`N/A
`
`Adequate
`
`Adequate
`
`N/A
`
`Adequate
`
`#16: How Supplied/Storage and Handling (21CFR 201.57(c)(17))
`
`The white opaque 140 mg capsules marked with “ibr 140 mg” in black ink are available in white
`HDPE bottles with a child-resistant closure:
`
`
`
`90 capsules per bottle: NDC 57962-140-09
`
`(b) (4)
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`

`QUALITY ASSESSMENT
`
`
`
`120 capsules per bottle: NDC 57962-140-12
`
`Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between
`15°C and 30°C (59°F to 86°F). Retain in original package until dispensing.
`
`The IMBRUVICA (ibrutinib) tablets are supplied in 4 strengths in the following packaging
`configurations:
`
`• 140 mg tablets: Yellow green to green round tablets debossed with “ibr” on one side and “140”
`on the other side. Carton of one folded blister card containing two 14-count blister strips for a
`total of 28 tablets: NDC 57962-014-28
`
`• 280 mg tablets: Purple oblong tablets debossed with “ibr” on one side and “280” on the other
`side. Carton of one folded blister card containing two 14-count blister strips for a total of 28
`tablets: NDC 57962-280-28
`
`• 420 mg tablets: Yellow green to green oblong tablets debossed with “ibr” on one side and “420”
`on the other side. Carton of one folded blister card containing two 14-count blister strips for a
`total of 28 tablets: NDC 57962-420-28
`
`• 560 mg tablets: Yellow to orange oblong tablets debossed with “ibr” on one side and “560” on
`the other side. Carton of one folded blister card containing two 14-count blister strips for a total
`of 28 tablets: NDC 57962-560-28
`
`Store tablets in original packaging at room temperature 20°C to 25°C (68°F to 77°F). Excursions
`are permitted between 15°C and 30°C (59°F to 86°F).
`
`Item
`Strength of dosage form
`
`Available units (e.g., bottles of
`100 tablets)
`
`Information Provided in NDA
`Capsule 140 mg
`Tablets: 140 mg, 280 mg, 420 mg and
`560 mg
`Capsules: bottles of 90; bottles of 120
`Tablets: Carton of one folded blister
`card containing two 14-count blister
`strips for a total of 28 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
`
`Provided
`
`N/A
`Store tablets in original packaging at
`room temperature 20°C to 25°C
`(68°F to 77°F). Excursions are
`permitted between 15°C and 30°C
`(59°F to 86°F).
`
`Conclusion: Adequate
`
`Reviewer’s Assessment
`
`Adequate
`
`Adequate
`
`Adequate
`
`N/A
`
`Adequate
`
`

`

`QUALITY ASSESSMENT
`
`Manufacturer/distributor name listed at the end of PI, following Section #17
`
`Active ingredient made in China.
`
`Distributed and Marketed by:
`Pharmacyclics LLC
`Sunnyvale, CA USA 94085
`and
`Marketed by:
`Janssen Biotech, Inc.
`Horsham, PA USA 19044
`
`Item
`Manufacturer/distributor name
`(21 CFR 201.1)
`
`Information Provided in NDA
`Provided
`
`Reviewer’s Assessment
`Adequate
`
`Conclusion: Adequate
`
`Carton Labeling
`
`3 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`Comments on the Information Provided
`in NDA
`
`Conclusions
`
`Imbruvica®
`(ibrutinib) tablets
`
`Adequate
`
`140 mg, 280 mg, 420 mg, 560 mg
`
`Adequate
`
`Take IMRUVICA tablet by mouth
`
`Adequate
`
`Provided
`
`Adequate
`
`“See accompanying literature for dosage
`information”
`(PI inserted in the carton)
`
`Adequate
`
`Reserved space
`
`Reserved space
`
`Provided
`
`Provided
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Provided
`
`Adequate
`
`Provided
`
`Provided
`
`Adequate
`
`Adequate
`
`Adequate
`
`tem
`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))
`Route of
`administration
`21.CFR
`201.100(b)(3))
`Net contents* (21 CFR
`201.51(a))
`Name of all inactive
`ingredients (;
`Quantitative
`ingredient
`information is
`required for
`injectables) 21CFR
`201.100(b)(5)**
`Lot number per 21
`CFR 201.18
`Expiration date per 21
`CFR 201.17
`“Rx only” statement
`per 21 CFR
`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
`manufacturer/distribut
`or
`(21 CFR 201.1)
`Others
`
`

`

`QUALITY ASSESSMENT
`
` Reviewer’s Assessment: Adequate
`
`List of Deficiencies: None
`
`Primary Drug Product Reviewer Name and Date:
`
`Xing Wang, Ph.D., ONDP/DNDPI/NDPBII
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`Anamitro Banerjee, Ph.D., Acting Branch Chief, ONDP/DNDPI/NDPBII
`
`

`

`Xing
`Wang
`
`Anamitro
`Banerjee
`
`Digitally signed by Xing Wang
`Date: 1/04/2018 09:08:49PM
`GUID: 525daca300039122a4daaad45e49c6fb
`
`Digitally signed by Anamitro Banerjee
`Date: 1/04/2018 10:53:36PM
`GUID: 5075764700003844b7bc89632228509f
`
`31 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`
`
`
`Application No.
`
`Type of Submission
`
`Applicant/Sponsor
`
`Product Name
`
`Dosage Form/Strength
`
`Route of Administration
`
`Intended Use
`
`Submission Date
`
`QUALITY ASSESSMENT
`
`
`
`
`BIOPHARMACEUTICS REVIEW
`
`NDA 210563-ORIG-1
`
`505(b)(1)/New dosage form and new strengths
`
`Pharmacyclics LLC
`
`
`Imbruvica® (Ibrutinib) Tablets
`
`Immediate Release Tablets, 140 mg, 280 mg, 420 mg, 560 mg
`
`Oral
`
`Treatment of lymphoma, leukemia and chronic graft versus host
`disease
`
`08/31/2017 (Original Submission)
`
`10/20/2017 (Quality Amendment Response to IR)
`
`
`
`Primary Reviewer
`
`Om Anand, Ph.D.
`
`Secondary Reviewer
`
`Okpo Eradiri, Ph.D.
`
`1. EXECUTIVE SUMMARY
`
`
`
`Background: NDA 210563 for Imbruvica® (Ibrutinib) Tablets, 140 mg, 280 mg, 420 mg, 560 mg is a
`505(b)(1) submission. Ibrutinib is a first-in-class, orally administered, potent small-molecule, and
`inhibitor of Bruton’s tyrosine kinase (BTK), a mediator of critical B-cell signaling pathways implica ted
`in the pathogenesis of B-cell cancers. Previously, Imbruvica® (Ibrutinib) capsules have been approved
`in NDA205552 which are available in only 140 mg strength. The recommended adult dose for ibrutinib
`is 560 mg (4x140 mg capsules once daily) for patients with MCL and 420 mg (3x140 mg capsules once
`daily) for patients with chronic lymphocytic leukemia (CLL) or Waldenstrom’s macroglobuline mia
`(WM). Pharmacyclics has developed new
` filmcoated tablet formulation of ibrutinib (in
`140 mg, 280 mg, 420 mg, and 560 mg strengths) which is the subject of the Review of this NDA.
`
`
`Review Summary: The Biopharmaceutics review is focused on the evaluation of the data supporting
`the proposed dissolution method and acceptance criterion, biowaiver request and the bridging between
`the proposed commercial product and the product used in the clinical studies.
`
`
`
`
`
`1
`
`(b) (4)
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`
`
`
`
`
`Dissolution method: ACCEPTABLE
`
`
`The following proposed dissolution methods are acceptable:
`
`
`
`Apparatus
`
`Speed
`
`Volume
`
`Medium
`
`USP 2
`(paddle)
`
`USP 2
`(paddle)
`
`75 rpm
`
`900 mL
`
`75 rpm
`
`900 mL
`
`For 140 and 280 mg strengths
`
`3.0% w/v Tween 20 in 0.05 M potassium phosphate buffer,
`pH 6.8@37.0± 0.5° C
`
`For 420 and 560 mg strengths
`6.0% w/v Tween 20 in 0.05 M potassium phosphate buffer,
`pH 6.8@37.0± 0.5° C
`
`
`
`
`Dissolution Acceptance Criterion: ACCEPTABLE
`
`The dissolution acceptance criterion of Q= % at 45 minutes for all strengths of Ibrutinib Tablets is
`acceptable.
`
`Biowaiver Request: ACCEPTABLE
`
`The Applicant’s biowaiver request for intermediate strengths (280 mg and 420 mg) is granted.
`
`Bridging: ACCEPTABLE
`
`The bridging between the proposed commercial product and the product used in the clinical studies is
`acceptable.
`
`Discriminating ability of the dissolution method:
`
`The Applicant has adequately studied the discriminating ability of the proposed dissolution method.
`
`The dissolution method can clearly discriminate the formulations manufactured using
`drug substance,
`. The dissolution method can
`also pick up the changes occurring in the release profile of Ibrutinib Tablets during stress conditions
`(40° C/75% RH). Though there is no clear discrimination, there is a rank order in the dissolut io n
`profiles of Ibrutinib Tablets
`. The method is not
`discriminating with regard to minor formulation changes.
`
`Recommendation:
`
`From a Biopharmaceutics perspective, NDA 210563 for Imbruvica® (Ibrutinib) Tablets, 140 mg, 280
`mg, 420 mg, 560 mg is recommended for APPROVAL
`
`
`
`
`
`
`
`2
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`QUALITY ASSESSMENT
`
`
`2. List of submissions reviewed:
`
`
`
`
`
`
`eCTD sequence # Received date Document
`
`Original NDA submission
`Quality/Response to Quality/Biopharmaceutics Information
`
`Request
`
`0001
`
`0014
`
`08/31/2017
`
`10/20/2017
`
`
`
`3. Highlight Key Outstanding Issues from Last Cycle: None
`
`
`4. Concise Description Outstanding Issues Remaining: None
`
`5. BCS designation:
`
`As per the Applicant, Ibrutinib is a Biopharmaceutical Classification System (BCS) Class 2 compound
`(low solubility/high permeability) and is practically insoluble to slightly soluble in water and aqueous
`buffered solutions. In a human-derived Caco 2 model the in-vitro permeability of ibrutinib was determined
`to be high (apparent permeability [A to B] = 57.9 × 10-6 cm/s, efflux ratio = 0.13. In addition, the extent of
`absorption in humans for ibrutinib was determined to be ≥ 90%, demonstrating high permeability (refer
`Ibrutinib capsule NDA 205552).
`The solubility values obtained for ibrutinib in various aqueous media are provided in Table 1; the results
`indicate that ibrutinib is practically insoluble to slightly soluble in aqueous solutions. This solubilit y
`increases with decreasing pH, but the compound remains practically insoluble in the pH region between 3
`and 8. Ibrutinib solubility in water as a function of pH is presented below in Figure 1.
`
`
`Table 1: Ibrutinib Solubility in Aqueous Media as a Function of pH
`
`
`
`
`
`
`
`
`
`
`3
`
`

`

`
`
`
`
`
`
`
`QUALITY ASSESSMENT
`
`
`
`Figure 1: Ibrutinib solubility in water as a function of pH
`
`
`
`
`
`
`
`
`
`
`As shown in Figure 1, Ibrutinib is poorly soluble in water, however, when protonated (pKa = 3.7-4.0), the
`solubility of ibrutinib in water is much higher. The solubility of ibrutinib is ~1.6 mg/mL at pH 1, 0.003
`mg/mL in 10 mM ammonium acetate pH 4.5 and 0.003 mg/mL in 10 mM ammonium acetate at pH 8.
`
`6. Polymorphism:
`
`
`
`7. Particle Size:
`
`Ibrutinib is very slightly soluble in aqueous solutions, therefore particle size may affect dissolution rate
`and subsequently systemic absorption. The particle size specification of
` ibrutinib used
`throughout formulation and process development is the same as that used for the approved capsules
`(D[v, 0.9] = not more than
`µm). The commercial ibrutinib tablets will be manufactured with
`ibrutinib of the same particle size specification as the approved 140 mg capsules.
`
`
`8. Formulation:
`
`The drug product is an imme