`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`205552Orig2s000
`CHEMISTRY REVIEW(S)
`
`
`

`

`
`
`N205552 Review #2
`
`1
`
`NBA 205-552
`
`Imbruvica (ibrutinib) capsules, 140 mg
`
`Pharmacyclics, Inc.
`
`Xiao—Hong Chen, Ph.D.
`Donghao (Robert) Lu, Ph.D.
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`
`CMC Review of NBA 205-552
`
`For the Division of Oncology Drug Products I (HFD-150)
`
`Reference ID: 3392746
`
`

`

`
`
`N205552 Review #2
`
`2
`
`Table of Contents
`
`Table of Contents .......................................................................................................................... 2
`
`Chemistry Review Data Sheet...................................................................................................... 3
`
`The Executive Summary .............................................................................................................. 7
`
`I. Recommendations ..................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability..................................................... 7
`
`B. Recommendation on Post Marketing Requirements, Post Marketing Commitments,
`Agreements, and/or Risk Management Steps, if Approvable....................................... 7
`
`II. Summary of Chemistry Assessments ..................................................................................... 7
`
`A. Description of the Drug Product(s) and Drug Substance(s) ......................................... 7
`
`B. Description of How the Drug Product is Intended to be Used ...................................... 9
`
`C. Basis for Approvability Recommendation ...................................................................... 9
`
`III. Administrative ........................................................................................................................9
`
`A. Reviewer’s Signature ........................................................................................................ 9
`
`B. Endorsement Block ........................................................................................................... 9
`
`C. CC Block ............................................................................................................................ 9
`
`Chemistry Assessment ................................................................................................................. 10
`
`Appendix ....................................................................................................................................... 11
`
`Reference ID: 3392746
`
`

`

`NDA 205-552 CMC Review #2
`
`Chemistry Review Data Sheet
`
`1. NDA 205-552
`
`2. REVIEW #2:
`
`3. REVIEW DATE: 17-OCT—2013
`
`4. REVIEWER: Donghao (Robert) Lu, Ph.D. (Drug substance)
`Xiao—Hong Chen, Ph.D. (Drug product)
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 5 1 Reviewed
`
`Document Date
`
`Original NDA submission
`Amendment SN0018
`Amendment SN0021
`Amendment SN0027
`Amendment SN0029
`
`28-Jun-2013
`09-Aug-2013
`13-Aug-2013
`23-Aug-2013
`29-Aug-2013
`
`7. NAME & ADDRESS OF APPLICANT:
`
`NAME:
`
`_
`ADDRESS
`
`Phannacyclics, Inc.
`
`995 East Arques Avenue,
`Sunnyvale, CA 94085
`
`REPRESENTATIVE:
`
`Christine Salido, Exec. Director,
`
`TELEPHONE:
`
`Regulatory Affairs
`
`(408) 215-3476
`
`8. DRUG PRODUCT NANIE/CODE/TYPE:
`
`Imbruvica®
`a) Proprietary Name:
`b) Non-Proprietary Name a}SAN):
`
`ibrutinib
`
`Reference ID: 3392746
`
`

`

`NDA 205-552 CMC Review #2
`
`4
`
`c) Code Name/# PCI-32765, JNJ 54179060
`d) Chem. Type/Submission Priority (ONDC only):
` Chem. Type: 1
` Submission Priority: P
`
`9. LEGAL BASIS FOR SUBMISSION: Filed 505(b)(1)
`
`10. PHARMACOL. CATEGORY: A potent small-molecule covalent
`inhibitor of Bruton’s tyrosine kinase
`
`11. DOSAGE FORM:
`
`Capsule
`
`12. STRENGTH/POTENCY:
`
` 140 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED: _X_Rx ___OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
` SPOTS product – Form Completed
`
` X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`Other Name:
`
`Name (USAN, INN):
`Name (CAS):
`
`Ibrutinib
`1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo
`[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one
`1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo
`[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one
`(CAS) Registry Num: 936563-96-1
`Mol. Formula:
`C25H24N6O2
`Mol. Wt.:
`440.50
`Structural Formula:
`
`Reference ID: 3392746
`
`

`

`NDA 205-552 CMC Review #2
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DMF #
`
`TYPE
`
`HOLDER
`
`ITEM REFERENCED
`
`CODE1
`
`STATUS2
`
`DATE
`REVIEW
`COMPLETED
`8-2-2013
`
`Adequate
`
`III
`
`III
`
`III
`
`III
`
`III
`
`4
`
`4
`
`3
`
`4
`
`3
`
`Adequate
`
`8-2-2013
`
`Adequate
`
`1-31-2012
`
`Adequate
`
`8-2-2013
`
`Adequate
`
`9-21-2012
`
`5
`
`COMMEN
`T
`USP<661>
`and FAR
`(21CFR177.
`1520)
`submitted in
`NDA
`USP<661>
`and FAR
`(21CFR177.
`1520)
`submitted in
`NDA
`Reviewed
`by Gene
`Holbert
`USP<661>
`and FAR
`(21CFR177.
`1210)
`submitted in
`NDA
`Reviewed by
`Raymond P.
`Frankewich
`
`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`3 – Reviewed previously and no revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other (explain under "Comments")
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need
`to be reviewed)
`
`B. Other Supporting Documents:
`
`Doc #
`
`OWNER
`
`ITEM
`REFERENCED
`
`STATUS
`
`DATE
`REVIEW
`COMPLETED
`
`COMMENTS
`
`C. Related Documents:
`
`DOCUMENT APPLICATI
`ON
`
`OWNER
`
`DESCRIPTION/COMMENT
`
`Reference ID: 3392746
`
`(b) (4)
`
`(b) (4)
`
`

`

`REVIEWER
`Office of Compliance
`John Duan, Ph.D.
`Sue Kang
`A methods validation request was
`sent and the evaluation results are
`pending. It should be noted that
`the approvability of the NDA is
`not dependent upon the results.
`Xiao Hong Chen
`
`13-SEP-2013
`
`9-JUL-2013
`
`Bryan S. Riley, Ph.D.
`
`NDA 205-552 CMC Review #2
`
`IND
`
`NUMBER
`102,688
`
`Pharmacyclics,
`Inc.
`
`Original IND submitted on 07-Oct-2008.
`
`6
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`CONSULTS
`RECOMMENDATION
`Acceptable
`Acceptable
`Acceptable
`Pending
`
`EES
`Biopharmaceutics
`Proprietary Name
`Methods Validation
`
`DATE
`17-OCT-2013
`25-SEP-2013
`16-AUG-2013
`23-JUL-2013
`
`EA (Categorical
`exclusion)
`Microbiology
`
`Acceptable
`
`Acceptable
`
`Reference ID: 3392746
`
`

`

`NDA 205-552 CMC Review #2
`
`7
`
`The Chemistry Review for NDA 205-552
`
`The Executive Summary
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From a CMC perspective, this application is recommended for Approval.
`
`EES has an overall “Acceptable” recommendation for this NDA. Refer to the EES report in
`the Appendix.
`
`Since the completion of the CMC review #1, the biopharmaceutics review of the
`dissolution specification has been finished and recommended “Approval” with a Post
`Marketing Commitment (PMC). The PMC requires the applicant to collect additional
`dissolution profile data (release and on stability) using the same USP Apparatus Type 2
`(Paddle) at 75 rpm in a different dissolution medium from that described in the NDA. The
`Applicant will use the overall dissolution data to set the final dissolution acceptance criteria.
`The final report submission for this PMC is due on February 1, 2015. Refer to Dr. John
`Duan’s review dated September 25, 2013 in darrts. Review of the package insert labeling
`and container/carton labels has been completed. The following comment should be
`included in the action letter:
`
`Based on the available stability data an 24-month expiry dating is granted for Imbruvica®
`ibrutinib capsules stored at temperature of 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).
`
`B. Recommendation on Post Marketing Requirements, Post Marketing
`Commitments, Agreements, and/or Risk Management Steps, if Approvable.
`
`N/A.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Product
`Ibrutinib is being co-developed by Pharmacyclics, Inc. (Pharmacyclics) and Janssen Research &
`Development, LLC (Janssen R&D) as an orally administered anticancer agent for the treatment
`of a variety of B-cell malignancies, including mantle cell lymphoma (MCL) and chronic
`lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The drug product is an
`immediate-release opaque white size 0 hard gelatin capsule for oral administration, containing
`140 mg of ibrutinib drug substance and commonly used compendial excipients such as
`microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate,
`
`Reference ID: 3392746
`
`

`

`NDA 205-552 CMC Review #2
`
`etc. The drug product is packaged in two configurations: 160 cc HDPE bottles with
`an“) child-resistant closure containing 90 capsules and 200 cc HDPE bottles
`containing 120 capsules.
`
`mm The intended
`The drug product is manufactured by the contract manufacturer,
`commercial scale is
`M“) capsules (
`(m4) total weight). Manufacturing of Ibrutinib Caps'p‘les
`uses
`
`The drug product specifications consist of description, identity, assay, individual and total
`degradation products,
`(hm) content uniformity, dissolution and microbial limits. The
`HPLC method used for identity, assay and content uniformity is the same method that is used for
`the drug substance assay. The acceptance limits for the three identified degradation products
`have been qualified and/or below the safety threshold for oncology drugs per pharm/tox review
`team. The acceptance limits for degradation products
`mm per
`FDA’s cements. Dissolution specification is evaluated by biopharmaceutics reviewer, Dr. John
`Duan. His review is still ongoing. Microbial test is reviewed by microbiology reviewer, Dr.
`Bryan Riley; and an acceptable recommendation was made by his review (July 8, 2013).
`
`Stability studies for drug product are performed. Stability data for 3 registration batches, 7
`primary stability batches and one supportive stability batch are submitted. The drug product
`appears to be fairly stable. Only a slight increasing trend of degradation products
`(m4)
`and a slight decreasing trend of assay have been observed. Up to 24 months long term
`primary and supportive stability data are well within the specification. Six months of accelerated
`stability data also conform to the specification with a clearer trending for degradation products
`and assay value. Photostability study conducted per ICH guidelines showed that the drug product
`is not light sensitive. Based on the primary and supportive stability data the shelf life of 24
`months stored at “storage temperature at 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) can be granted.
`
`Drug Substance
`The drug substance is Ibrutinib. The chemical name is 1-{(3R)-3-[4-amino-3-(4-
`phenoxyphenyl)-1prrazolo [3 ,4-d]pyrimidin-l-yl]piperidin—l-yl}prop-Z-en-l-one. It has a
`molecular formula of C25H24N602 and its molecular weight is 440.50.
`
`Data from the studies of elemental analysis, UV, IR, NTVIR and MS demonstrated that the
`structure was adequately defined. The synthesis route and the use of reagents are adequate for the
`manufacturing of the ibrutinib drug substance.
`
`The impurities detected during the development and synthesis of the drug substance were
`evaluated. Analytical methods were developed for the control of the impurities listed in the
`submission. Comprehensive information for all the impurities at the starting material level, at the
`intermediate level and at the final synthesis level was adequately presented.
`
`Reference ID: 3392746
`
`

`

`NDA 205-552 CMC Review #2
`
`9
`
`Ibrutinib was subjected to heat, heat and moisture, light, and chemical stresses. The drug
`substance was physically and chemically stable based on evaluation of the testing data. The drug
`substance has a retest period of months.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Imbruvica® is administered by orally once daily for 560 mg (four 140 mg capsules) for MCL
`(Mantel cell lymphoma) patients and 420 mg (three 140 mg capsules) for CLL (Chronic
`Lymphocytic Leukemia) patients. Capsules should be taken orally with a glass of water without
`being opened, broken or chewed.
`
`C. Basis for Approvability Recommendation
`
`From a CMC perspective, Pharmacyclics, Inc. has submitted sufficient and appropriate
`information to support the approval of the drug product. There were several CMC concerns that
`were sent to the sponsor during the review process. Pharmacyclics has adequately addressed
`these CMC comments (see CMC review #1).
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`See appended electronic signature page.
`
`B. Endorsement Block
`
`Reviewer Name/Date: Xiao-Hong Chen, Ph.D.
`Donghao (Robert) Lu, Ph.D.
`Branch Chief Name/Date: Ali Al Hakim, Ph.D.
`
`C. CC Block
`
`Diane Hanner/OHOP/DHP/Regulatory PM
`Janice Brown/ONDQA/CMC Lead
`Jewell Martin/ONDQA/PM
`Donghao Lu/ONDQA/DNDQA I Branch II
`Ali Al Hakim/ONDQA/DNDQA I/Branch Chief
`Ramesh Sood/ONDQA/DNDQA I Acting Director
`
`Reference ID: 3392746
`
`(b)
`(4)
`
`11 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XIAO H CHEN
`10/18/2013
`
`DONGHAO R LU
`10/18/2013
`
`ALI H AL HAKIM
`10/18/2013
`
`Reference ID: 3392746
`
`

`

`
`
` Imbruvica (ibrutinib) Capsules
`
`NDA 205-552
`
`Summary Basis for Recommended Action
`Chemistry, Manufacturing, and Controls
`
`
`
`
`Applicant: Pharmacyclics, Inc.,
`
`995 East Arques Avenue
`Sunnyvale, CA 94085
`
`
`
`
`
`Indication: For the treatment of a variety of B-cell malignancies, including mantle cell
`lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic
`leukemia (CLL/SLL).
`
`
`Presentation: The product will be available as capsules in single 140 mg strength. The
`capsules are packaged in two configurations: 90 count in 160 cc HDPE
`bottles and 120 count in 200 cc HDPE bottles.
`
`EER Status: Pending
`
`Consults:
`
`ONDQA Biopharmaceutics – Acceptable as per Dr. John Duan’s review
`dated 26-Sep-13.
`
`Methods Validation – The methods were sent to FDA labs and the results
`from the lab are pending at this time. This does not affect the approvability
`recommendation.
`
`EA – Categorical exclusion granted.
`
`Microbiology- Acceptable (Bryan S. Riley, 9-Jul-13)
`
`
`
`
`
`
`Post-Approval Agreements/Commitment: The biopharm reviewer has recommended a
`post-approval commitment. The applicant will collect additional dissolution profile data
`using the recommended dissolution media from at least an additional ten batches through
`12 month of storage under long-term conditions. Based on these data, the applicant will
`set final dissolution acceptance criteria and submit this information under a supplement.
`The details have been included in the biopharm review by Dr. Duan.
`
`
`
`
`
`Reference ID: 3384888
`
`1
`
`

`

`Drug Substance:
`
`The drug substance, ibrutinib, is a new molecular entity. It has one chiral center with R—
`configuration, and a molecular weight of 440.5. The drug substance is a white to off-
`-
`(m4)
`(m4)
`white
`powder.
`
`The CMC information for the drug substance has been reviewed and found acceptable by
`the reviewer. The drug substance quality is ensured through appropriate controls for the
`starting materials, in-process controls throughout the manufacturing process and the
`appropriate final drug substance specification. The drug substance specification includes
`tests and acceptance criteria for drug substance critical quality attributes, e.g.,
`appearance, identification, assay, impurities, particle size distribution, crystal form,
`residual solvents, heavy metals, and residue on ignition. The analytical procedures have
`been adequately described and validated to control the quality of the drug substance. The
`stability of the drug substance has been demonstrated through appropriate stability
`studies to support a proposed retest period of «)months.
`
`Drug product:
`
`Imbruvica (ibrutinib) capsules are immediate release, hard gel capsules containing 140
`mg of the drug substance. The drug product formulation uses standard compendial
`excipients. The manufacturing process includes
`M“)
`The applicant has used conventional in-process
`controls with appropriate set points and ranges for the process parameters, and end
`product testing to control the quality of the drug product. The end product specification
`includes testing for appearance, identification, assay, content uniformity, dissolution,
`m“) microbial contents and degradation products. The analytical procedures
`for the drug product testing are adequately described and validated. The provided
`stability data support a proposed 24-month expiration period for this product.
`
`The drug product is stored at 20°C -25°C (GB-77°F). Excursions permitted 15-30°C (59—
`86°F).
`
`Conclusion: Adequate from CMC perspective.
`
`Additional Items:
`
`All associated Drug Master Files are acceptable or the pertinent information has been
`adequately provided in the application.
`
`Overall Conclusion: The final recommendation from the Office of Compliance (0C) is
`pending at the time of writing this memorandum. All CMC related issues have been
`resolved. The application is reconnnended for “Approval” from CMC perspective
`
`Reference ID: 3384888
`
`

`

`pending overall “Acceptable” recommendation from OC. A memorandum with final
`overall recommendation will be entered into DARRTS after the OC recommendation.
`
`
`
`Ramesh K. Sood, Ph.D.
`Division Director (Acting), DPA I/ONDQA
`
`
`
`
`
`Reference ID: 3384888
`
`3
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RAMESH K SOOD
`10/04/2013
`
`Reference ID: 3384888
`
`

`

`
`
`N205552 Review #1
`
`1
`
`NBA 205-552
`
`Imbruvica (ibrutinib) capsules, 140 mg
`
`Pharmacyclics, Inc.
`
`Xiao-Hong Chen, Ph.D.
`Donghao (Robert) Lu, Ph.D.
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`
`CMC Review of NBA 205-552
`
`For the Division of Oncology Drug Products I (HFD-150)
`
`Reference ID: 3377509
`
`

`

`
`
`N205552 Review #1
`
`2
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
`
`The Executive Summary .............................................................................................................. 8
`
`I. Recommendations ..................................................................................................................... 8
`
`A. Recommendation and Conclusion on Approvability .......................................................... 8
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable...................................................................................... 8
`
`II. Summary of Chemistry Assessments ..................................................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................... 8
`
`B. Description of How the Drug Product is Intended to be Used ............................................ 9
`
`C. Basis for Approvability Recommendation ........................................................................ 10
`
`III. Administrative ...................................................................................................................... 10
`
`A. Reviewer’s Signature ........................................................................................................ 10
`
`See appended electronic signature page. ................................................................................ 10
`
`B. Endorsement Block ........................................................................................................... 10
`
`C. CC Block........................................................................................................................... 10
`
`Chemist_r1 Assessment ................................................................................................................ 11
`
`I. Review Of Common Technical Document-Quality (CTD—Q) Module 3.2 ............................ 11
`
`s DRUG SUBSTANCE [Ibrutinib
`
`"’"" ..................................... 11
`
`3.1 General Information ................................................................................................ 11
`82 Manufacture [Ibrutinib
`(m4) .......................................... 12
`8.3 Characterization [Ibrutinib
`(m4) .................................... 20
`8.4 Control of Drug Substance [Ibrutinib
`(m4) .................... 30
`S5 Reference Standards or Materials [Ibrutinib
`(m4), USP] .................................. 43
`8.6 Container Closure Svstem ....................................................................................... 43
`S. 7
`Stability [Ibrutinib
`(m4) ................................................ 43
`P DRUG PRODUCT [Ibrutinib Capsules] .......................................................................... 47
`
`Pl Description and Composition of the Drug Product [Ibrutinib Capsules] ............... 47
`P2
`Pharmaceutical Development ................................................................................. 48
`
`Reference ID: 3377509
`
`

`

`
`
`N205552 Review #1
`
`3
`
`P3 Manufacture ............................................................................................................ 67
`
`R4 Control of Excipients .............................................................................................. 74
`P5 Control of Drug Product ......................................................................................... 76
`R6 Reference Standards or Materials ........................................................................... 95
`
`R7 Container Closure System....................................................................................... 95
`R8
`Stability ................................................................................................................... 97
`A APPENDICES ................................................................................................................ 109
`
`R REGIONAL INFORMATION ....................................................................................... 109
`
`II. Review Of Common Technical Document-Quality (CTD—Q) Module 1 ............................. 109
`
`A. Labeling & Package Insert .............................................................................................. 109
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................... 111
`
`III. List Of Deficiencies/Comments To Be Communicated ........................................................ 111
`
`Reference ID: 3377509
`
`

`

`NDA 205-552 CMC Review #1
`
`4
`
`Chemistry Review Data Sheet
`
`
`
`
`1. NDA 205-552
`
`2. REVIEW #1:
`
`3. REVIEW DATE: 13-SEPT-2013
`
`4. REVIEWER: Donghao (Robert) Lu, Ph.D. (Drug substance)
`
`
`
`Xiao-Hong Chen, Ph.D. (Drug product)
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Document Date
`
`
`Submission(s) Reviewed Document Date
`
`Original NDA submission 28-Jun-2013
`Amendment SN0018 09-Aug-2013
`Amendment SN0021 13-Aug-2013
`Amendment SN0027 23-Aug-2013
`Amendment SN0029 29-Aug-2013
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`NAME:
`
`ADDRESS:
`
`REPRESENTATIVE:
`
`TELEPHONE:
`
`Pharmacyclics, Inc.
`995 East Arques Avenue,
`Sunnyvale, CA 94085
`
`Christine Salido, Exec. Director,
`Regulatory Affairs
`(408) 215-3476
`
`
`
`
`
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`a) Proprietary Name: Imbruvica®
`b) Non-Proprietary Name (USAN): ibrutinib
`
`Reference ID: 3377509
`
`

`

`NDA 205-552 CMC Review #1
`
`5
`
`c) Code Name/# PCI-32765, JNJ 54179060
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 1
`• Submission Priority: P
`
`
`9. LEGAL BASIS FOR SUBMISSION: Filed 505(b)(1)
`
`
`10. PHARMACOL. CATEGORY: A potent small-molecule covalent
`inhibitor of Bruton’s tyrosine kinase
`
` Capsule
`
`
`11. DOSAGE FORM:
`
`12. STRENGTH/POTENCY: 140 mg
`
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`
`14. Rx/OTC DISPENSED: _X_Rx ___OTC
`
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`
`
` SPOTS product – Form Completed
`
` X Not a SPOTS product
`
`
`
`
`
`
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`Name (USAN, INN):
`Name (CAS):
`
`Ibrutinib
`1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo
`[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one
`1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo
`[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one
`(CAS) Registry Num: 936563-96-1
`C25H24N6O2
`Mol. Formula:
`Mol. Wt.:
`
`440.50
`
`Structural Formula:
`
`Other Name:
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3377509
`
`
`
`

`

`NDA 205-552 CMC Review #1
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`DMF # TYPE
`
`HOLDER
`
`ITEM REFERENCED
`
`CODE1
`
`STATUS2
`
`DATE
`REVIEW
`COMPLETED
`8-2-2013
`
`Adequate
`
`III
`
`III
`
`III
`
`III
`
`III
`
`4
`
`4
`
`3
`
`4
`
`3
`
`Adequate
`
`8-2-2013
`
`Adequate
`
`
`Adequate
`
`
`1-31-2012
`
`8-2-2013
`
`Adequate
`
`
`9-21-2012
`
`6
`
`COMMEN
`T
`USP<661>
`and FAR
`(21CFR177.
`1520)
`submitted in
`NDA
`USP<661>
`and FAR
`(21CFR177.
`1520)
`submitted in
`NDA
`Reviewed
`by Gene
`Holbert
`USP<661>
`and FAR
`(21CFR177.
`1210)
`submitted in
`NDA
`Reviewed by
`Raymond P.
`Frankewich
`
`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`3 – Reviewed previously and no revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other (explain under "Comments")
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need
`to be reviewed)
`
`
`B. Other Supporting Documents:
`
`Doc #
`
`OWNER
`
`ITEM
`REFERENCED
`
`STATUS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DATE
`REVIEW
`COMPLETED
`
`
`
`
`
`COMMENTS
`
`
`
`
`
`
`
`
`C. Related Documents:
`
`DOCUMENT APPLICATI
`ON
`
`OWNER
`
`DESCRIPTION/COMMENT
`
`Reference ID: 3377509
`
`(b) (4)
`
`(b) (4)
`
`

`

`7
`
`Original IND submitted on 07-Oct-2008.
`
`
`
`DATE
`13-SEP-2013
`13-SEP-2013
`16-AUG-2013
`23-JUL-2013
`
`13-SEP-2013
`
`REVIEWER
`Office of Compliance
`John Duan, Ph.D.
`Sue Kang
`A methods validation request was
`sent and the evaluation results are
`pending. It should be noted that
`the approvability of the NDA is
`not dependent upon the results.
`Xiao Hong Chen
`
`9-JUL-2013
`
`Bryan S. Riley, Ph.D.
`
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`CONSULTS
`RECOMMENDATION
`EES
`Pending
`Biopharmaceutics
`Pending
`Proprietary Name
`Acceptable
`Methods Validation
`Pending
`
`NDA 205-552 CMC Review #1
`
`IND
`
`NUMBER
`102,688
`
`
`
`
`
`Pharmacyclics,
`Inc.
`
`
`EA (Categorical
`exclusion)
`Microbiology
`
`
`Acceptable
`
`Acceptable
`
`Reference ID: 3377509
`
`

`

`NDA 205-552 CMC Review #1
`
`The Chemistry Review for NDA 205-552
`
`The Executive Summary
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From a CMC perspective, this application is reconnnended for Approval pending the
`overall recommendation for the pre-approval inspection from the Office of Compliance.
`
`In addition, the biophannaceutics review of the dissolution specification is still pending.
`Review of the package insert labeling and container/carton labels are under way. The
`following comment should be included in the action letter:
`
`Based on the available stability data an 24-month erpirv dating is grantedfor Imbruvica®
`
`ibrutiuib capsules stored at temperature of20 °C to 25°C (68 ‘77 to 77°F) with excursions
`
`permitted between 15°C and 30°C (between 59 OF and 86°F).
`
`B. Recommendation on Post Marketing Requirements, Post Marketing
`Commitments, Agreements, and/or Risk Management Steps, if Approvable.
`
`N/A.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Product
`Ibrutinib is being co-developed by Pharmacyclics, Inc. (Pharmacyclics) and Janssen Research &
`Development, LLC (Janssen R&D) as an orally administered anticancer agent for the treatment
`of a variety of B-cell malignancies, including mantle cell lymphoma (MCL) and chronic
`lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The drug product18 an
`immediate-release opaque White size 0 hard gelatin capsule for oral administration, containing
`140 mg of ibrutinib drug substance and commonly used compendial excipients such as
`microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate,
`etc. The drug product is packaged in two configurations: 160 cc HDPE bottles with
`(no) child-resistant closure containing 90 capsules and 200 cc HDPE bottles
`containing 120 capsules.
`
`mm) The intended
`The drug product is manufactured by the contract manufacturer,
`commercial scale is
`(m4) capsules
`(m4) total weight). Manufacturing of Ibrutinib Capsules
`(1.) (4)
`use
`
`Reference ID: 3377509
`
`

`

`NDA 205-552 CMC Review #1
`
`(b) (4)
`
`The drug product specifications consist of description, identity, assay, individual and total
`degradation products,
`M“) content uniformity, dissolution and microbial limits. The
`HPLC method used for identity, assay and content uniformity is the same method that is used for
`the drug substance assay. The acceptance limits for the three identified degradation products
`have been qualified and/or below the safety threshold for oncology drugs per pharm/tox review
`team. The acceptance limits for degradation products
`(mm per
`FDA’s comments. Dissolution specification is evaluated by biophannaceutics reviewer, Dr. John
`Duan. His review is still ongoing. Microbial test is reviewed by microbiology reviewer, Dr.
`Bryan Riley; and an acceptable recommendation was made by his review (July 8, 2013).
`
`Stability studies for drug product are performed. Stability data for 3 registration batches, 7
`primary stability batches and one supportive stability batch are submitted. The drug product
`appears to be fairly stable. Only a slight increasing trend of degradation products
`M“)
`and a slight decreasing trend of assay have been observed. Up to 24 months long term
`primary and supportive stability data are well within the specification. Six months of accelerated
`stability data also conform to the specification with a clearer trending for degradation products
`and assay value. Photostability study conducted per ICH guidelines showed that the drug product
`is not light sensitive. Based on the primary and supportive stability data the shelf life of 24
`
`months stored at “storage temperature at 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) can be granted.
`
`Drug Substance
`The drug substance is Ibrutinib. The chemical name is l—{(3R)—3-[4—amino—3-(4—
`phenoxyphenyl)-1prrazolo [3,4-d]pyrimidin-l-yl]piperidin-1-yl}prop-2-en-l-one. It has a
`molecular formula of C25H24N502 and its molecular weight is 440.50.
`
`Data from the studies of elemental analysis, UV, IR, NMR and MS demonstrated that the
`structure was adequately defined. The synthesis route and the use of reagents are adequate for the
`manufacturing of the ibrutinib drug substance.
`
`The impurities detected during the development and synthesis of the drug substance were
`evaluated. Analytical methods were developed for the control of the impurities listed in the
`submission. Comprehensive information for all the impurities at the starting material level, at the
`intermediate level and at the final synthesis level was adequately presented.
`Ibrutinib was subjected to heat, hea