`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203341Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`ONDQA Division Director’s Memo
`NDA 203341, Bosulif® (bosutinib) Tablets
`Date: 27-JUL-2012
`
`Introduction
`BOSULIF (bosutinib) Tablets are immediate-release tablets supplied in two strengths (100 and
`500 mg). BOSULIF is indicated for the treatment of patients with relapsed or refractory chronic,
`accelerated or blast phase chronic myeloid leukemia. The daily dose is 500 mg, which may be
`either escalated (up to 600 mg) or reduced based on patient response and/or toxicity. Dose
`adjustments will occur using the developed dosage strengths, and tablets will not be altered for
`dosing adjustments.
`
`ONDQA recommends approval of this NDA. There are no outstanding CMC deficiencies for
`this NDA.
`
`Administrative
`The original submission of this 505(b)(1) NDA was received 17-NOV-2011 from Wyeth
`Pharmaceuticals, Inc. (Collegeville, PA). Several solicited CMC amendments were also
`reviewed during the review cycle. The Chemistry, Manufacturing and Controls assessment is
`captured in the following reviews, respectively: Chemistry Reviews #1 and #2 (by Dr. J. Crich,
`dated 18-JUL-2012 and 23-JUL-2012, respectively), and the ONDQA Biopharmaceutics Review
`#1 (by Dr. A. Khairuzzaman, dated 15-MAY-2012).
`
`The NDA is supported by IND 68,268 and nine (9) drug master files (DMFs). Primary CMC
`reviews, including the ONDQA Biopharmaceutics review, confirm approval recommendations,
`and all primary reviews confirm that there are no outstanding CMC deficiencies.
`
`An overall acceptable recommendation from the Office of Compliance was received on 10-MAY-
`2012. Acceptable labeling, including container/carton labels, was negotiated and finalized during
`the review clock.
`
`
`
`The following language needs to be placed into the action letter:
`An expiration dating period of 24 months is granted for the drug product, when stored at 25°C
`(77°F) excursions permitted between 15°C to 30°C (59°F to 86°F).
`
`
`
`
`Reference ID: 3165829
`
`

`

`Drug Substance (bosutinib)
`Chemical Name: 3—Quinolinecarbonitrile, 4-[(2.4-dichloro—5-methoxyphenyl)arnino]—6—methoxy—
`7-[3—(4—methyl—l-piperazinyl) propoxy]—, hydrate (1 :1)
`
`HM
`
`OMe
`
`0M0
`
`Me’ N
`
`N/
`
`' HzO
`
`Bosutinib is a new molecular entity. It is a white to yellowish tan powder. It is classified as a
`BCS Class 4 compound (low solubility, low permeability) with pH-dependent solubility. It is
`nonhygroscopic. The morphic fonn selected for development and commercialization
`(m4)
`
`(5) (4)
`
`Detailed information regarding the designation of
`“M" starting materials, the commercial sources, acceptance criteria. and associated
`the
`methods of analysis are provided and were determined to be acceptable during the review.
`
`A Quality by Design (QbD) approach was employed for the manufacturing process based on the
`principles outlined in ICH Q8, Q9 and Q11, including the development of a quality target product
`profile (QTPP), identification of the potential critical quality attributes (CQAs), and the
`designation of operating ranges for each step of the process. The Applicant used a statistically
`designed multivariate experimental (DoEs) approach to propose the overall operating ranges and
`control strategy for the manufacturing process. The quality attributes of bosutinib monohydrate
`are defined in the drug substance specification based on a traditional approach. The key and
`critical process parameters and ranges for each manufacturing step are provided. as well as the
`regulatory commitment for handling movements associated with the operating ranges for these.
`The Applicant’s approach was deemed to be acceptable as changes to other parameters would be
`reported in accordance with 21 CFR 314.70 (see pages 15-19 of Chemistry Review #1).
`
`(m4) is granted for the drug substance, when packaged in
`The proposed r‘e—test period 01
`the proposed container closure system and stored at controlled room temperature.
`
`Drug Product (Tablets, 100 and 500 mg)
`Bosulif® (bosutinib) Tablets are available in 100 mg and 500 mg dosage strengths. The
`tablets contain bosumib monohydrate as the active pharmaceutical ingredient (equivalent to 100
`mg and 500 mg of anhydrous bosutinib). Excipients include microcrystalline cellulose,
`croscarmellose sodium. poloxamer, povidone, magnesium stearate. polyvinyl alcohol, titanium
`dioxide, polyethylene glycol, talc, and an iron oxide coloring component (yellow for the 100 mg
`
`Reference ID: 31 65829
`
`

`

`tablet, and red for the 500 mg tablet). All excipients are conventional for solid oral dosage
`forms.
`(m4)
`
`(5) (4)
`
`Standard release specifications for a solid oral dosage form are proposed.
`The commercial packaging is 60—count HDPE bottles. The Applicant proposed a 24 month
`expiry for this product when stored in the commercial packaging at 25°C (77°F); excursions
`permitted to 15-30°C (59-86°F). Based on the stability data provided, the Agency grants a 24
`month expiry for the drug product. as packaged in the commercial configuration and when stored
`at USP controlled room temperature.
`
`The proposed commercial container closure system for both strengths consists of a 60-mL HDPE
`polyethylene bottle/closure with dessicant. The 100 mg tablets will be packaged in a 120—count
`configuration, while the 500 mg tablets will be packaged in a 30-count configuration. The
`Applicant employed a matrixed stability protocol design conducted on 100-count configurations
`of both dosage strengths. The original NDA included stability data from three primary batches
`for both dosage strengths, covering up to 24 months at 25°C/60% RH and 30°C/75% RH. and up
`to 6 months at 40°C/75% RH. As stated in Chemistry Review #1 (page 10). the provided data
`support the proposed 24 month expiration dating period for both strengths of the drug product as
`packaged in HDPE bottles and stored at controlled room temperature.
`
`Chemistry Review #1 (pages 187-191) also notes that here are difl'erences in the proposed
`container/closure system intended for marketing and that used in the primary stability studies.
`Therefore. the reviewer assessed the comparability of the primary stability configuration with that
`proposed for commercialization as part of the review. The Applicant provided calculations for
`moisture absorption capacity of desiccant canister and total available moisture within the
`commercial container closure system to justify the proposed shelf life in the proposed commercial
`container closure system. The configurations were determined to be sufficiently comparable, and
`the provided stability data package was determined to be acceptable in support of the proposed
`expiration dating period of 24 months.
`
`Due to the lack of stability data for the proposed commercial configuration. the Agency requested
`revisions to the Applicant’s post-approval stability protocol based on ICH Q1A(R2) (see pages
`191-193 of Chemistry Review #1). Specifically. the Agency requested that the post approval
`stability commitment include a 6—month accelerated study along with the long-term studies to be
`conducted through the proposed shelf life for the first three production batches of bosutinib (both
`dosage strengths). The requested revisions had not been received by the Agency at the time of
`finalization for Chemistry Review #1. and therefore, the recommendation at that time was for a
`Complete Response pending resolution of the final post approval stability protocol. Chemistry
`Review #2 confirms that the Applicant’s post approval stability protocol had been revised
`appropriately, and the deficiency was satisfactorily resolved.
`
`During the review. the chemistry team discussed multiple options regarding the possible
`resolution of the post approval stability protocol. including the filing mechanism for updated
`stability data generated from the protocol itself (see pages 193-194 in Chemistry Review #1).
`The issue was ultimately discussed by the inclusive team in a 16-JUL-2012 internal meeting.
`Attendees included Dr. J. Crich. Dr. D. Ghosh, Ms. J. Brown, and Dr. S. Pope Miksinski. These
`discussions are captured in Chemistry Review #1. At the conclusion of this meeting, all attendees
`
`Reference ID: 31 65829
`
`

`

`agreed that the deficiency noted in the post approval stability protocol did not impart a significant
`risk to overall product quality. The identified review issue was satisfactorily resolved in
`Chemistry Review #2, in which the reviewer confirms the acceptability of the revised post
`approval stability protocol (pages 13-14).
`
`Final labeling negotiations included discussion regarding the Applicant’s proposed statement of
`“MADE IN SPAIN” on the container labels. The CMC team deferred a final determination on
`this issue to the Office of Compliance (Ms. Jean McCue), who confirmed that the statement
`should be retained for conformance with current US Customs requirements. Please refer to page
`14 of Chemistry Review #2 for additional information.
`
`Please place the following language in the action letter:
`An expiration dating period of 24 months is granted for the drug product, when stored at 25°C
`(77°F) excursions permitted between 15°C to 30°C (59°F to 86°F).
`
`Reference ID: 3165829
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SARAH P MIKSINSKI
`07/27/2012
`
`Reference ID: 3165829
`
`

`

`
`
`NDA 203341
`
`Bosulit‘ (bosutinib) Tablets
`
`Wyeth Pharmaceuticals, Inc.
`(a Wholly Owned Subsidiary of Pfizer, Inc.)
`
`CMC Review # 2
`
`Joyce Crich, Ph.D
`
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`Branch II
`
`CMC REVIEW OF NDA 203341
`
`For the Division of Hematology Products
`
`Reference ID: 3163817
`
`

`

`
`
`Table of Contents
`
`CMC Review Data Sheet .........................................................................................3
`
`The Executive Summary .........................................................................................7
`
`I. Recommendations ...................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 7
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps, if Approvable ................................................................................................... 7
`
`II. Summary of CMC 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 ....................................................... 10
`
`C. Basis for Approvability or Not-Approval Recommendation ......................................................... 10
`
`III. Administrative.......................................................................................................................... 1 1
`
`CMC Assessment.................................................................................................... 12
`
`
`1. Postapproval Stability Commitment .....
`2. Container labels ..................................................................................................................................................... 14
`
`Reference ID: 3163817
`
`Page 2 of 14
`
`CMC Review #2
`
`

`

`
`
`CMC Review Data Sheet
`
`CMC Review Data Sheet
`
`1. NDA 203341
`
`2. REVIEW #:2
`
`3. REVIEW DATE: 23-July—2012
`
`4. REVIEWER: Joyce Crich, Ph.D
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Original IND 68,268 submission
`Original IND 68,268 CMC review
`CMC end-of-phase-2 meeting (10-Jul-2008) minutes
`CM Review #1 for NDA 203341
`
`Document Date
`
`19-Apr-2004
`24-May-2004
`01-Aug-2008
`20—J
`-2012
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`DARRTS
`
`Submission(s) Reviewed
`
`SD
`Number
`
`Document Date
`
`Stamp Date
`
`OriinalNDA Submission - 17-Nov-2011
`
`17-Nov-2011
`
`Amendment (Resoonse to 26—Jan-2012 CMC IR — 06-Mar—2012
`
`re ' ardm dissolutlon
`
`re - uest
`
`Updated Drug Product Analytical Methods and
`Validation of
`1 ca] Procedures
`giggidlglent (BC) (Responseto FDA 23-Mar-2012
`Dru Product Manufacturer Information Ute
`
`Amendment (Response to 03-May-2012 CMC IR
`and 16-Ar-2012 IRreHardin microbial uri
`Amendment esonse to 24-Ma 2012telecon
`
`Amendment (Updated post-approval stability
`protocols for DP --response to 18-Jul-2012 CMC
`
`12
`
`_
`_
`19 Mar 2012
`05_APR_2012
`03-Ma -2012
`
`06-Mar—2012
`
`_
`_
`19 Mar 2012
`05_APR_2012
`03-Ma -2012
`
`16 MAY 2012
`31-MAY-2012
`
`16 MAY 2012
`31-MAY-2012
`
`22
`
`19-Jul-2012
`
`19-Jul-2012
`
`Reference ID: 3163817
`
`Page 3 of 14
`
`CMC Review #2
`
`

`

`
`
`CMC Review Data Sheet
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address:
`Representative:
`
`Telephone:
`
`Wyeth Pharmaceuticals, Inc.
`(a Wholly Owned Subsidiary of Pfizer, Inc.)
`500 Arcola Road, Collegeville, PA 19426-3982
`Carl M. DeJuliis, PharmD,
`Director, Worldwide Regulatory Strategy
`(860) 441 - 1693
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: BosulitQ
`b) Non-Proprietary Name: bosutinib tablets
`c) Code Name/# (ONDQA only): bosutinib monohydrate (drug substance)
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 1 (new molecular entity)
`
`0 Submission Priority: S (stande review)
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY: Dual Src Bcr-Abl tyrosine kinase inhibitor
`
`11. DOSAGE FORM:
`
`tablet
`
`12. STRENGTH/POTENCY:
`
`100 mg and 500 mg
`
`13. ROUTE OF ADMINISTRATION: oral
`
`14. Rx/OTC DISPENSED:
`
`‘l Rx
`
`OTC
`
`15. SPOTS {SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM):
`
`SPOTS product — Form Completed
`
`\I
`
`Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Reference ID: 3163817
`
`Page 4 of 14
`
`CMC Review #2
`
`

`

`CMC REVIEW OF NDA 203341
`
`CMC Review Data Sheet
`
`Molecular Formula
`
`Molecular Weight
`
`C25H29C12N503°H20
`
`548.46 (monohydrate)
`530.46 anh drous
`
`United States Ado ted Name
`
`S ‘
`
`bosutinib monoh drate
`
`Chemical Name
`
`3-Quinolinecarbonitrile 4-[(2.4-dichloro—5-
`methoxyphenyl)amino]-6-n1ethoxy—7-[3-(4-methyl—l-piperazinyl)
`
`Chemical Abstracts Service
`
`CAS Reis Number
`
`CAS-380843- 75-4
`
`17. RELATED/SUPPORTING DOCUNIENTS:
`
`A. DMFs:
`
`
`
`
`2841352012
`
`See sections
`141 & 3.2.P..41
`S
`ti
`
`28-Feb-20 12
`
`1.4.1 & 3.2.P.7
`
`Rev'
`ed
`17-Feb-2012 mkefhmgi
`R '
`ed
`17-Feb-2012 Dfikefhonzyu
`RC.
`.33....
`Reviewed by
`11-Mar-2005 Dr. Gene Holbert
`&
`& Dr. Edwin Jao
`
`09-Sep-2003
`
`See sections
`1.4.1 & 3.2.P.7
`
`Adequate
`
`Adequate
`
`23-Jun-2006
`
`Reviewed by
`Josephine Jee
`See sections
`3.2.P.2.4 &
`3.2.P.7
`
`1 Action codes for DMF Table:
`l — DMF Reviewed.
`
`Reference ID: 3163817
`
`Page 5 of 14
`
`CMC Review #2
`
`

`

`
`
`CMC Review Data Sheet
`
`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 Documents:
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`_
`
`18. STATUS:
`
`0NDQA:
`
`CONSULTS/ CMC
`
`EEEEEEEEEVEEWE RECOMNDAHON m
`
`————
`Acceptable
`10-ME-2012
`
`Pharm/Tox
`
`Impurity limits in drug
`substance are acc table
`
`17-Jul-2012
`
`Shwu Luan Lee
`
`15-Ma -2012
`
`————
`Methods Validation
`Acceptable
`04—May-2012
`Daniel J Mans
`
`
`
`DMEPA*
`
`Microbiology
`
`The proposed proprietary
`name, Bosulif is acc table
`
`03-Feb-2012
`
`Kimberly De Fronzo
`
`Categorical exclusion
`accepted (see CMC
`Review #1
`
`approval fiom
`microbiology product
`auali
`stand 0 oint
`
`20-Jul-2012
`
`Joyce Crich
`
`12-Jun-2012
`
`Robert Mello
`
`*DIVIEPA: Division of Medication Error Prevention and Analysis
`
`Reference ID: 3163817
`
`Page 6 of 14
`
`CMC Review #2
`
`

`

`
`
`CMC Assessment Section
`
`The CMC Review for NDA 203341
`
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From the chemistry, manufacturing and controls standpoint, this NDA is recommended for
`approval. There are no outstanding CMC issues that impact approvability of this NDA.
`
`Include the following language in the approval letter:
`Based on the provided stability data, a 24-month expiration dating period is granted for the
`drug product bosutinib tablets (100 mg and 500 mg) when stored at USP controlled room
`temperature 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F).
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`II. Summary of CMC Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`(1) Drug Substance
`
`The drug substance bosutinib is a new molecular entity. Detailed information regarding
`the drug substance is provided in the NDA.
`
`(b) (4)
`
`(m4)
`Detailed information regarding designation of the
`starting materials. the commercial sources, acceptance criteria, and associated methods
`of analysis are provided.
`
`A Quality by Design (QbD) approach was employed for the manufacturing process
`based on the principles of ICH Q8, Q9 and Q1 1, including quality target product
`profile (QTPP), identification of the potential critical quality attributes (CQAs), the
`process parameters (CPP, KPP) that have a potential impact on these CQAs, and
`operating spaces for each step of the drug substance manufacturing process by
`statistically designed multivariate experimental (DoEs) approaches, leading to the
`overall operating space and control strategy for the manufacturing process. The
`quality attributes of bosutinib monohydrate are defined in the drug substance
`
`Reference ID: 3163817
`
`Page 7 of 14
`
`CMC Review #2
`
`

`

`
`
`CMC Assessment Section
`
`specification based on a traditional approach. The key and critical process
`parameters for each manufacturing step are provided, as well as the regulatory
`commitment for the operating range.
`
`Bosutinib monohydrate is a white to yellowish tan powder. It is classified as a BCS
`Class 4 compormd (low soluble and low permeable material) with pH de endent
`solubility. It is non-hygroscopic. The selected polymorph form
`a” 4) of bosutinib
`monohydrate for development and commercialization is the
`«0(4)
`
`(we) when
`The submitted stability data support the proposed retest period of
`packaged in the proposed container system and stored at controlled room temperature.
`
`(2) Drug Product
`
`Bosulit® (bosutinib) tablets are available in 100 mg and 500 mg dosage strengths. The
`tablets contain bosutinib monohydrate as the active pharmaceutical ingredient
`equivalent to 100 mg and 500 mg of bosutinib anhydrous together with
`microcrystalline cellulose, croscannellose sodium, poloxamer, povidone,
`magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc,
`and iron oxide yellow (for 100 mg tablet) and iron oxide red (for 500 mg tgk‘let).
`
`Bosulit® (bosutinib) tablets are available for oral administration in two strengths: a
`100 mg yellow, oval-shaped, biconvex, immediate release fihn coated tablet with
`debossed with “Pfizer” on one side and “100” on the other; Bosutinib film coated
`
`tablets, a 500 mg red, oval-shaped, biconvex immediate release film coated tablet
`with “Pfizer” on one side and “500” on the other. Bosulifm (bosutinib) tablets are
`supplied in 60 ml HDPE bottles of 120 tablets for 100 mg strength and of 30 tablets
`for 500 mg strength.
`
`(5) (4)
`
`The applicant submitted the stability data from three primary batches for the 100 mg
`strength and 500 mg strength tablets up to 24 months at 25°C/60% RH and 30°C/75%
`RH, and up to 6months at 40°C/75% RH in the primary stability container closure
`system. Those stability data support the proposed 24 months shelf-life for the drug
`
`Reference ID: 3163817
`
`Page 8 of 14
`
`CMC Review #2
`
`

`

`
`
`CMC Assessment Section
`
`product in both strengths packaged in I-IDPE bottles and stored at controlled room
`temperature. Additionally, the submitted photostability study results on the primary lots
`indicate that the drug product does not require protection fiom light.
`
`The NDA submission did not include any stability data for the proposed commercial
`container closure system which is difl'erent from the primary stability container closure
`system (e. g. configuration, fill volume, headspace, MVTR, and amount of desiccant).
`According to ONDQA’s Initial Quality Assessment and Filling Review for this NDA
`dated 21-Dec-2011 in DARRTS, the issue of lacking stability data for the proposed
`commercial container closure system was determined as a review issue. Dining this
`review cycle, instead of providing any stability data for the proposed commercial
`container closure system after Agency’s information request for such data, the applicant
`provided the calculations for moisture absorption capacity of desiccant canister and
`total available moisture within the commercial container closure system to justify
`the proposed shelf life in the proposed commercial container closure system. The
`provided justification appears to be reasonable, but it does not completely exclude
`possible impact on quality attributes linked to water content due to the potential
`difference in moisture level control. Although the risk of changing container closure
`system for solid dosage form is relatively low, the provided theoretical calculation
`of moisture exposure (MVTR vs. desiccant capacity) is only a supporting data for
`moisture-barrier equivalence, and is not a replacement for stability study result from
`the proposed container closure system. According to ICH Q1A(R2) Section
`II(B)(4), Stability testing should be conducted on the dosage form packaged in the
`container closure system proposed for marketing. Therefore, it is recommended that
`the Postapproval Stability Commitment be revised to include accelerated studies for
`6 months along with the long-term studies through the proposed shelf life for the
`first three production batches of bosutinib 100 mg and 500 mg tablets, to monitor
`the stability trend and to confirm the shelf life, based on ICH Q1A(R2) Section
`II(B)(8) (refer to the Letter of Information Request dated 18-Jul-2012). The
`applicant provided adequate response and revised the Postapproval Stability
`Commitment accordingly in the Amendment of 19-Jul-2012.
`
`The recommendation and conclusion on the approvability for this NDA are made by
`incorporating QBD principle, risk management, and scientific rationale based on the
`stability data from the primary stability study container closure system, provided that
`the firm committed to conduct the postapporval stability studies and to monitor the
`stability of marketed drug products in the proposed commercial container closure
`system according to ICH Q1A(R2) H(B)(8) (refer to revised the Postapproval
`Stability Commitment in Section P.8.2). The CMC reviewer does not think this
`special situation with relative low risk to product quality (under the circumstance of
`lacking stability data for the proposed commercial container closure system at filing
`was determined as a review issue) should be viewed as a precedent in general for other
`future NDA submissions as any scenario of container closure system varies from each
`other and very much depends on the nature of drug product.
`
`Reference ID: 3163817
`
`Page 9 of 14
`
`CMC Review #2
`
`

`

`
`
`CMC Assessment Section
`
`B. Description of How the Drug Product is Intended to be Used
`
`Bosulit® (bosutinib) Tablets are indicated for the treatment of chronic, accelerated, or
`blast phase Ph+ chronic myelogenous leukemia (CML) in adult patients with resistance,
`or intolerance to prior therapy.
`
`Bosulit® (bosutinib) Tablets are dosed orally with food. The recommended dose and
`schedule of Bosulif is 500 mg once daily. Dose adjustments may be required for
`hematologic and non—hematologic adverse reactions.
`
`. Basis for Approvability or Not-Approval Recommendation
`
`The applicant provided adequate response to Agency’s Letter of Information Request
`dated 18-Jul-2012 and revised the Postapproval stability commitment accordingly in
`the Amendment of 19-Jul-2012. The deficiency identified as the basis for a Not-
`Approval Recommendation in CMC Review #1 has been addressed satisfactorily.
`
`Adequate data have been provided for the manufacture and controls of the drug substance
`and drug product. The microbiology reviewer has determined that the drug product is
`acceptable from the microbiology perspective.
`
`The Division of Medication Error Prevention and Analysis (DMEPA) has no objections to
`the use of the proposed proprietary name Bosulif.
`
`Methods validation was completed on 04—May—2012 by the FDA St. Louis Laboratory for
`the drug substance and drug product analysis which are confirmed to be acceptable for
`quality control and regulatory purposes. Note: it is not required for approval of the NDA.
`
`The CMC revisions of the package insert have been incorporated into the revised labeling
`during the labeling meetings of the NDA. The revised container labels, as amended by the
`applicant on 10-Jul-2012 are acceptable from the CMC perspective.
`
`The Office of Compliance issued an overall “acceptable” recommendation dated 10-
`May—2012 for all facilities used for manufacturing and control of the drug substance
`and drug product.
`
`Reference ID: 3163817
`
`Page 10 of 14
`
`CMC Review #2
`
`

`

`
`
`CMC Assessment Section
`
`III. Administrative
`
`A. Reviewer’s Signature:
`(See appended electronic signature page)
`
`Joyce Crich, Ph.D, Reviewer, ONDQA
`
`B. Endorsement Block:
`
`(See appended electronic signature page)
`
`Debasis Ghosh, Ph.D., Acting CMC Lead, Division of New Drug Quality Assessment
`I, Office of New Drug Quality Assessment (ONDQA)
`
`Janice Brown, Acting Branch Chief, Branch II, Division ofNew Drug Quality
`Assessment I (DNDQA I), ONDQA
`
`C. CC Block: entered electronically in DARRTS
`
`3 Pages Have Been Withheld In Full As b4 (CCI/TS) Immediately Following This Page
`
`Reference ID: 3163817
`
`Page 11 of 14
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`CMC Review #2
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOYCE Z CRICH
`07/24/2012
`
`JANICE T BROWN
`07/24/2012
`
`Reference ID: 3163817
`
`

`

`
`
`NDA 203341
`
`Bosulit‘ (bosutinib) Tablets
`
`Wyeth Pharmaceuticals, Inc.
`(a Wholly Owned Subsidiary of Pfizer, Inc.)
`
`Joyce Crich, Ph.D
`
`Review Chemist
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`Branch II
`
`CMC REVIEW OF NDA 203341
`
`For the Division of Hematology Products
`
`Reference ID: 3161772
`
`

`

` CMC REVIEW OF NDA 203341
`hm V
`
`Table of Contents
`
`CMC Review Data Sheet .........................................................................................4
`
`The Executive Summary8
`
`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 CMC 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 ....................................................... 11
`
`C. Basis for Approvability or Not-Approval Recommendation ......................................................... 11
`
`III. Administrative.......................................................................................................................... 12
`
`CMCAssessment13
`
`I. Review Of Common Technical Document—Quality (Ctd—Q) Module 3.2: Body Of Data ....... 13
`
`S. DRUG SUBSTANCE .................................................................................................................... 13
`S. 1
`General Information .................................................................................................................... 13
`8.1.1
`Nomenclature ..................................
`8.1.2
`Structure......................................
`
`
`
`General Properties ...........................
`Manufacture ...................................
`Manufacturers .................................................................................................................................. 14
`
`Description of Manufacturing Process and Process Controls....
`...................................................... 14
`Control of Materials ......................................................................................................................... 23
`
`Controls of Critical Steps and Intermediates............................................................................ 32
`Process Validation and/or Evaluation ...................................................................................... 36
`
`Manufacturing Process Development ........................................................................................................ 37
`Characterization .............................................................................................................................. 72
`Elucidation of Structure and other Characteristics .................................................................................. 72
`
`S 1.3
`S.2
`8.2.1
`
`8.2.2
`8.2.3
`
`8.2.4
`8.2.5
`
`8.2.6
`8.3
`8.3.1
`
`Impurities ................................................................................................................................................ 79
`8.3.2
`Control of Drug Substance ................................................................................................... 85
`8.4
`Specification ............................................................................................................................... 85
`8.4.1
`8.4.2 & 8.4.3 Analytical Procedures & Validation ofAnalytical Procedures ................................................. 91
`8.4.4
`Batch Analyses ............................................................................................................................. 105
`8.4.5
`Justification of Specification................................................................................................................. 108
`8.5
`Reference Standards or Materials ................................................................................................. 11 5
`
`
`
`
`
`8.6
`8.6.1.
`8.6.2.
`8.6.3.
`S. 7
`8.7.1
`8.7.2
`S 7.3
`
`Container Closure System............................................................................................................. 11 7
`Description of the Container Closure System ...................................................................................... 117
`Specifications .....................................................................
`
`Analytical Procedures .................
`Stability ..................................................................................................................................... 1 1 8
`
`Stability Summary and Conclusions .................................................................................................... 118
`Postapproval Stability Protocol and Stability Commitment...
`........................ 121
`Stability Data ........................................................................................................................................... 123
`
`Reference ID: 3161772
`
`Page 2 of 209
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`CMC Review #1
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`:52}
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`CMC REVIEW OF NDA 203341
`
`Ill-i!!!"
`
`P. DRUG PRODUCT ...................................................................................................................... 125
`
`R]
`P2
`P.2.l
`P.2.2
`P.2.3
`P.2.4
`P.2.5
`P.2.6
`P3
`P.3.l
`R32
`
`P.3.4
`P.3.5
`
`Description and Composition of the Drug Product ....................................................................... 125
`Pharmaceutical Development............................