`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`202570Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
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`

`

`
`
`ONDQA Division Director’s Memo
`NDA 202570, XALKORI (crizotinib) Capsules, 200 and 250 mg
`Date: 04-AUG-2011
`
`Introduction
`XALKORI (crizotinib) capsules are hard gelatin capsules supplied in two strengths (200 mg and
`250 mg). A
` is used for capsule filling, and all excipients are compendial. The
`200 mg capsules will be provided as white opaque/pink opaque hard gelatin capsules with “CRZ
`200” printed on the body and “Pfizer” printed on the cap. The 250 mg strength capsules will be
`provided as pink opaque/pink opaque hard gelatin capsules with “CRZ 250” and “Pfizer” printed
`on body and cap, respectively. Both will be packaged in HDPE bottles with child-resistant caps
`(60 count/bottle).
`
`XALKORI capsules are proposed for treatment of Anaplastic lymphoma kinase (ALK)-positive
`advanced non-small cell lung cancer (NSCLC). The recommended dose is 250 mg twice daily,
`with or without food. The capsules should be swallowed whole.
`
`“XALKORI” was confirmed as a conditionally acceptable trade name in a 23-JUN-2011 review
`by the Division of Medication Errors Prevention and Analysis (DMEPA). The proposed trade
`name was confirmed as acceptable in an updated 03-AUG-2011 DMEPA review.
`
`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 30-MAR-2011 from Pfizer, Inc.
`(San Diego, CA). Three (3) solicited CMC amendments were also reviewed during the review
`cycle. The Chemistry, Manufacturing and Controls assessment is captured in the following
`reviews, respectively: Chemistry Review #1 for both drug substance and drug product (dated 03-
`AUG-2011 and 02-AUG-2011, respectively), Chemistry Review for Analytical Methodology
`(02-AUG-20110), Biopharmaceutics Review #1 (dated 26-JUL-2011), and Biostatistics Review
`(dated 27-JUL-2011).
`
`The NDA is supported by IND 73,544 and ten (10) drug master files (DMFs). Primary CMC
`reviews for both drug substance and drug product, as well as biopharmaceutics, confirm an
`approval recommendation, and all primary reviews confirm that there are no outstanding CMC
`deficiencies. An acceptable overall recommendation from the Office of Compliance was
`provided on 03-AUG-2011. Supportive reviews of analytical methodology (Dr. R. Lu, review
`dated 02-AUG-2011) and biostatistics (Dr. M. Shen, review dated 27-JUL-2011) capture the
`assessment of application-specific Quality by Design (QbD) elements. The supportive reviews
`also confirm that there are no outstanding CMC deficiencies that would impact approvability.
`
`This NDA is recommended for approval from a Chemistry, Manufacturing and Controls
`standpoint.
`
`
`
`Reference ID: 2984281
`
`(b) (4)
`
`

`

`Drug Substance (Crizotinib)
`Chemical Name: (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-
`pyrazol-4-yl]pyridin-2-amine
`
`
`
`
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`
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`Crizotinib is a new molecular entity. It is a non-hygroscopic, white to pale yellow powder and
`insoluble in water. It possesses pKa values of 9.4 and 5.6, and it is highly soluble in acidic pH.
`Several polymorphic forms are possible, with
` as the most stable and as proposed for
`commercialization. The crizotinib structure contains one chiral center;
`
`
`
`Crizotinib
`
`
` The Applicant proposed a Quality by Design (QbD) approach to optimize the
`reaction conditions. This approach included the risk assessment, identification of critical quality
`attributes (CQA), material attributes (MA), critical and non-critical process parameters (CPP,
`NCPP), design space, control strategies, and change management.
`
` for
`The Applicant also proposed an Analytical Target Profile (ATP, HPLC method TM-
`assay and related substances) as part of the employed QbD approach. Based on evaluation of this
`element, the Agency determined that further discussions regarding the proposed ATP are needed
`before an approval recommendation can be made. The Applicant subsequently decided to
`withdraw the proposed ATP from the application.
`
` months when stored at the recommended container closure
`The proposed re-test period of
`system at ambient storage conditions is granted.
`
`
`Drug Product (Crizotinib Capsules, 200 and 250 mg)
`The drug product is manufactured
`
`
`
`
`
`
` All excipients used in the formulation are compendial and are
`conventional for solid oral dosage forms.
`
`The Applicant employed a risk-based, QbD approach to the development of crizotinib capsules.
`The Applicant defined of a quality target product profile (QTPP) along with critical quality
`
`
`
`Reference ID: 2984281
`
`
`
`
`
`(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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`(b) (4)
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`

`attributes (CQAs) for the drug product. DOE and risk assessment processes used throughout
`development defined the investigations performed to gain a thorough understanding of product
`quality. The investigations covered a wide range of input and material attributes as well as
`process parameters and led to a clear understanding of the relationships between, and impact of,
`the parameters investigated on the CQAs. The Applicant used this understanding to propose a
`design space that ensures delivery of drug product that consistently meets the required quality.
`The Applicant proposed a Method Operable Design Region (MODR) for the HPLC method TM-
` (identity, assay, impurities in drug product). This QbD element is approved as part of this
`application; it essentially mirrors USP criteria for chromatographic method adjustments. Specific
`reference is also made to the supporting review by the Office of Biostatistics (Dr. M Shen), which
`evaluated the statistical rationale used for the Applicant’s DOE studies and supporting statistical
`information related to the proposed MODR.
`
` month
`The commercial packaging is 60-count HDPE bottles. The Applicant proposed a
`expiry for this product when stored in the commercial packaging at 25ºC (77ºF); excursions
`permitted to 15-30ºC (59-86ºF).
`
`Based on the stability data provided, the Agency grants a fifteen (15) month expiry for the
`drug product, as packaged in the commercial configuration and when stored at USP
`controlled room temperature.
`
`Please include the drug product expiry in the action letter.
`
`Thank you,
`
`Richard (Rik) Lostritto, Ph.D., Director
`ONDQA, Division-I
`
`Reference ID: 2984281
`
`(b) (4)
`
`(b)
`(4)
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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/
`----------------------------------------------------
`
`RICHARD T LOSTRITTO
`08/04/2011
`
`Reference ID: 2984281
`
`

`

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`CHEMISTRY REVIEW
`
`NDA 202-570
`
`
`XALKORITM (crizotinib) Capsules
`
`(200 mg and 250 mg)
`
`
`Pfizer, Inc.
`
`
`
`
`Zedong Dong, Ph.D.
`
`Product Quality Reviewer
`DRUG PRODUCT
`
`Office of New Drug Quality Assessment, Division I
`
`
`
`CMC REVIEW OF NDA 202570 DRUG PRODUCT
`For the Division of Drug Oncology Products (HFD-150)
`
`
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`Reference ID: 2982826
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`

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`CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
`
`The Executive Summary .........................................................................................9
`
`I. Recommendations .......................................................................................................................9
`A. Recommendation and Conclusion on Approvability .......................................................................9
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable...................................................................................................9
`
`II. Summary of Chemistry Assessments.........................................................................................9
`A. Description of the Drug Product(s) and Drug Substance(s) .............................................................9
`B. Description of How the Drug Product is Intended to be Used........................................................12
`C. Basis for Approvability or Not-Approval Recommendation..........................................................12
`
`III. Administrative.........................................................................................................................12
`A. Reviewer’s Signature......................................................................................................................12
`B. Endorsement Block.........................................................................................................................12
`C. CC Block ........................................................................................................................................12
`
`Chemistry Assessment ...........................................................................................13
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.......13
`S
` DRUG SUBSTANCE...................................................................................................................13
`P
` DRUG PRODUCT .......................................................................................................................13
`P.1 Description and Composition of the Drug Product ......................................................................................... 13
`P.2
`Pharmaceutical Development.......................................................................................................................... 16
`P.3
`Manufacture .................................................................................................................................................... 44
`P.4
`Control of Excipients ...................................................................................................................................... 48
`P.5
`Control of Drug Product.................................................................................................................................. 50
`P.6
`Reference Standards or Materials.................................................................................................................... 60
`P.7
`Container Closure............................................................................................................................................ 61
`P.8
`Stability........................................................................................................................................................... 62
`A APPENDICES ...............................................................................................................................70
`R REGIONAL INFORMATION ......................................................................................................70
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ..................................71
`A. Labeling & Package Insert ..........................................................................................................71
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`Reference ID: 2982826
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`

`

`
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................73
`
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`CHEMISTRY REVIEW
`
`III. List Of Deficiencies To Be Communicated.............................................................................73
`
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`Reference ID: 2982826
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`

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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Chemistry Review Data Sheet
`
`
`1. NDA 202-570
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: August 2, 2011
`
`4. REVIEWER: Zedong Dong, Ph.D.
`
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`Original IND 73544 submission
`Original IND 73544 CMC review by Ying Wang
`CMC only pre-NDA meeting
`Pre-NDA Meeting Minutes
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED (CMC):
`
`
`Document Date
`12/12/ 2005
`02/10/2006
`10/29/2010
`11/12/2010
`
`Document Date
`
`03/30/2011
`06/29/2011
`
`07/13/2011
`07/20/2011
`07/27/2011
`07/29/2011
`
`Submission(s) Reviewed
`
`Original Submission 0002
`Amendment 0021 (Drug Product 9-Month
`Stability)
`Amendment 0028 (Labeling)
`Amendment 0029 (Response to CMC IR)
`Amendment 0033 (Response to CMC IR)
`Amendment 0035 (Response to CMC IR)
`
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`Name:
`
`Address:
`
`Pfizer, Inc.
`10646 Science Center Drive
`San Diego, CA 92121
`
`Reference ID: 2982826
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`Page 4 of 73
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Representative:
`
`Telephone:
`
`Ron Domingo
`
`(858) 622-3234
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`a) Proprietary Name: XALKORITM
`b) Non-Proprietary Name (USAN): Crizotinib
`c) Code Name/# (ONDC only): PF-02341066
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 1
`• Submission Priority: P
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY: ALK-positive advanced non-small cell lung
`cancer (NSCLC)
`
`
`11. DOSAGE FORM: Capsule
`
`12. STRENGTH/POTENCY: 200 mg and 250 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
`
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`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`
`Chemical Names:
`
`IUPAC: (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-
`yl]pyridin-2-amine
`
`CAS: 3-[(1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl)-1H-pyrazol-4-
`yl]-2-pyridinamine
`
`Reference ID: 2982826
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`Page 5 of 73
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`Molecular Formula: C21H22Cl2FN5O
`
`Molecular Weight: 450.34 Daltons
`
`
`Crizotinib
`
`
`
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`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`
`
`
`DMF
`#
`
`TYPE
`
`HOLDER
`
`IV
`
`IV
`
`III
`III
`
`III
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`III
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`III
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`III
`
`ITEM
`REFERENCED CODE1 STATUS2
`3
`Adequate
`
`DATE
`REVIEW
`COMPLETED
`06/09/2010
`
`3
`
`4
`3
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`4
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`4
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`4
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`4
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`Adequate
`
`10/29/2010
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`N/A
`Adequate
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`N/A
`07/07/2010
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`N/A
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`N/A
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`N/A
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`N/A
`
`N/A
`
`N/A
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`N/A
`
`N/A
`
`COMMENTS
`
`By Dr.
`Deepika Arora
`in NDA 22-
`368
`By Dr. Sharon
`Kelly
`N/A
`By Dr.
`Caroline
`Strasinger
`
`N/A
`
`N/A
`
`N/A
`
`N/A
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`Reference ID: 2982826
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`Page 6 of 73
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`(b) (4)
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`III
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`III
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`4
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`3
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`N/A
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`N/A
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`N/A
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`Adequate
`
`06/23/2006
`
`By Dr.
`Josephine Jee
`
`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 adequate data in the application, therefore the DMF was
`not reviewed)
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`B. Other Documents:
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`DOCUMENT
`N/A
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`18. STATUS:
`
`
`ONDQA:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Biostatistics
`EES
`Pharm/Tox
`Biopharm
`Analytical
`LNC
`Methods Validation
`
`DMEPA
`EA
`
`Reference ID: 2982826
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`APPLICATION NUMBER
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`DESCRIPTION
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`See body of text
`Pending
`N/A
`Approval
`Approval
`N/A
`N/A, according to the
`current ONDQA policy
`N/A
`Category exclusion (see
`review)
`
`7/27/2011
`
`
`07/26/2011
`08/02/2011
`
`
`
`Meiyu Shen
`Shawn Gould
`
`Kareen Riviere
`Donghao (Robert) Lu
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`Microbiology
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Approval
`
`08/01/2011
`
`Stephen Langille
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`Reference ID: 2982826
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`CHEMISTRY REVIEW
`Executive Summary Section
`The Chemistry Review for NDA 202-570
`
`The Executive Summary
`
` I. Recommendations
`
`
`Recommendation and Conclusion on Approvability
`
`A.
`
`NDA 202-570 is recommended for approval from a Chemistry, Manufacturing and
`Controls standpoint, pending satisfactory resolution of the Labeling and EES issues.
`
`B.
`
`Recommendation on Phase 4 (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:
`
`The commercial crizotinib drug product is a hard gelatin capsule formulation in two
`strengths (200 mg and 250 mg), with a
` being used for capsule filling.
`The excipients (including the components in gelatin capsule shell and printing ink) used
`for manufacturing the drug product are all compendial grade. Crizotinib capsules 200
`mg will be provided as white opaque/pink opaque hard gelatin capsules with “CRZ
`200” printed on the body and “Pfizer” printed on the cap. The 250 mg strength will be
`provided as pink opaque/pink opaque hard gelatin capsules with “CRZ 250” and
`“Pfizer” printed on body and cap, respectively. The drug product will be packaged in
`HDPE bottles with child-resistant caps (60 counts/bottle).
`
`Three formulations (powder in capsule (PIC), immediate release tablet, and intravenous
`solution) were used in clinical trials prior to the commercial capsule. The PIC
`formulation (10 mg, 50 mg, and 100 mg) was used for early stage Phase I studies. The
` drug loading,
`immediate release tablet (50 mg and 100 mg) formulation, with
`was later developed to meet the increased demand for further clinical trials. However,
`due to the lower drug loading of the tablet, the commercial capsule formulation was
`developed for administration convenience. The tablets and capsules use qualitatively
`similar excipients. The IV solution was developed for use in the absolute
`bioavailability study.
`
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`Reference ID: 2982826
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`Page 9 of 73
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`CHEMISTRY REVIEW
`Executive Summary Section
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`The crizotinib drug product is manufactured
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` Satisfactory batch analysis results were
`provided for one registration batch of 200 mg strength (batch# 9806533000) and three
`registration batches of 250 mg strength (batch# 9806683000, 9806633000, and
`9806683001).
`
`Nine-month stability results for the registration batches were submitted for storage
`under 25°C/60% RH, 30°C/75% RH, and 40°C/75% RH for the proposed commercial
`packaging configurations.
`
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` Based on the stability results, the
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`Page 10 of 73
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`Reference ID: 2982826
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`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
`recommended expiry for the crizotinib drug product is fifteen months. The applicant
`commits to placing the first three commercial scale batches of drug product on stability
`to confirm shelf life. In addition, annual production batches will be selected for
`stability testing at a rate of at least one batch per year per strength per packaging
`configuration according to the submitted post-approval stability protocol.
`
`Per Dr. Donghao Lu’s review on analytical methods and validation, the proposed
`commitment on Analytical Target Profile (ATP) is withdrawn from the application.
`The proposed Method Operable Design Regions (MODR) for the HPLC methods TM-
` (for identity, assay and impurities in drug product) and TM-
` (for assay
`and impurities in drug substance) are acceptable.
`
`Immediate container labeling was submitted for the 60 counts/bottle packaging
`configuration, which appears acceptable.
`
`Claim for category exclusion is granted per 21 CFR Part 25.31 (b).
`
`Drug Substance:
`(reproduced from Dr. Debasis Ghosh’s Review)
`
`Crizotinib, the drug substance, is a New Molecular Entity (NME). It is an inhibitor of
`ALK receptor tyrosine kinase. It is indicated for the treatment of ALK positive
`advanced non-small cell lung cancer (NSCLC). It is a non-hygroscopic, white to pale
`yellow powder and insoluble in water. It has pKa values of 9.4 and 5.6 and it is highly
`soluble in acidic pH. Several polymorphic forms are possible. However, the
` is
`stable and it is the proposed commercial form. It has one chiral center and
` Its structure was elucidated by IR, 1HNMR, 13CNMR, MS,
`UV/Vis, optical rotation and X-ray crystallography.
`
`Crizotinib
`
`
`
`
`
`
`
`. The applicant proposed a Quality by Design (QbD)
`approach to optimize the reaction conditions. The QbD approach led to the risk
`assessment, identification of critical quality attributes (CQA), material attributes (MA),
`critical and non-critical process parameters (CPP, NCPP), design space, control
`strategies, and change management. The applicant used the principles of ICHQ8, Q9
`and Q10 to develop QbD approach.
`
`To assure the identity, strength, purity, and quality, the crizotinib is controlled by the
`acceptance criteria of quality attributes including identification, assay, impurities, and
`particle size. Stability studies with crizotinib indicate that it is sensitive to strong acid,
`strong base, intense light and oxidation conditions. However, the related substance
`impurity and degradation products are well controlled by specification. The applicant
`proposed a retest period of
` months. Based on the principles of ICHQ1E and the risk
`
`Reference ID: 2982826
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`Page 11 of 73
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`CHEMISTRY REVIEW
`Executive Summary Section
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`
`
` months at long-term storage condition
`assessment, the retest period of
`(25oC/60%RH) is granted at this time.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Crizotinib capsules are available in 200 mg and 250 mg strengths in 60 counts/bottle
`packaging configuration. The capsules are recommended to be stored at 25°C (77°F),
`with excursions permitted to 15°C - 30°C (59°F - 86°F). A fifteen-month expiry at the
`proposed storage conditions will be granted based on the provided stability data. This is
`to be communicated to the applicant in the action letter.
`
`C. Basis for Approvability or Not-Approval Recommendation (Harmonized with DS
`review)
`
`
`This new drug application (202-570) is recommended to be approved from the CMC
`perspective pending an overall recommendation of the cGMP status of the
`manufacturing and testing facilities from the Office of Compliance. The
`recommendation for approval is based upon the acceptable identity, strength, quality,
`and purity upon the evaluation of the drug substance and drug product.
`
`
`III. Administrative
`
`
`A. Reviewer’s Signature
`
`
`(see appended electronic signature page)
`
`Zedong Dong, Ph.D.
`Chemistry Reviewer
`Division I, ONDQA
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`B. Endorsement Block
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`
`
`(see appended electronic signature page)
`
`Sarah Pope Miksinski, Ph.D.,
`Branch Chief
`Brach II, Division I, ONDQA
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`Rik Lostritto, Ph.D.
`Division Director
`Division I, ONDQA
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`C. CC Block: entered electronically in DARRTS
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`
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`Reference ID: 2982826
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`Page 12 of 73
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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.
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`/s/
`----------------------------------------------------
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`ZEDONG DONG
`08/02/2011
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`RICHARD T LOSTRITTO
`08/02/2011
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`Reference ID: 2982826
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`Crizotinib
`Capsule
`200 mg and 250 mg
`
`
`Pfizer Inc.
`
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`
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`CMC Reviewer
`(Analytical sections)
`
`Donghao (Robert) Lu, Ph.D.
`
`Division I of Pre-Marketing Assessment
`Office of New Drug Quality Assessment
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`
`
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`Reference ID: 2982813
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`36 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
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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.
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`/s/
`----------------------------------------------------
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`DONGHAO R LU
`08/02/2011
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`RICHARD T LOSTRITTO
`08/02/2011
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`Reference ID: 2982813
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`

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`CMC REVIEW
`
`NDA 202570
`
`
`Xalkori™
`(crizotinib) Capsules
` 200 mg & 250 mg
`
`
`Pfizer, Inc.
`
`
`
`
`Debasis Ghosh, M. Pharm., Ph.D.
`
`Product Quality Reviewer
`DRUG SUBSTANCE
`
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`Branch II
`
`
`CMC REVIEW OF NDA 202570 DRUG SUBSTANCE
`For the Division of Drug Oncology Products (HFD-150)
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`Reference ID: 2982868
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`CMC REVIEW OF NDA 202-570
`
`
`
`Table of Contents
`
`
`CMC 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 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....................................................... 10
`C. Basis for Approvability or Not-Approval Recommendation......................................................... 11
`III. Administrative..........................................................................................................................11
`CMC Assessment....................................................................................................12
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.......12
`S. DRUG SUBSTANCE.................................................................................................................... 12
`S.1
`General Information........................................................................................................................12
`S.1.1 Nomenclature............................................................................................................................................. 12
`S.1.2
`Structure..................................................................................................................................................... 12
`S 1.3 General Properties...................................................................................................................................... 13
`S.2
`Manufacture ....................................................................................................................................14
`S.2.1 Manufacturers ............................................................................................................................................ 14
`S.2.2 Description of Manufacturing Process and Process Controls..................................................................... 15
`S.2.3
`Control of Materials................................................................................................................................... 19
`S.2.4
`Controls of Critical Steps and Intermediates.............................................................................................. 24
`S.2.5
`Process Validation and/or Evaluation ........................................................................................................ 26
`S.2.6 Manufacturing Process Development ........................................................................................................ 26
`S.3
`Characterization ..............................................................................................................................54
`S.3.1
`Elucidation of Structure and other Characteristics..................................................................................... 54
`S.3.2
`Impurities................................................................................................................................................... 60
`S.4
`Control of Drug Substance..............................................................................................................66
`S.4.1
`Specification .............................................................................................................................................. 66
`S.4.2
`Analytical Procedures ................................................................................................................................ 67
`S.4.3
`Validation of Analytical Procedures .......................................................................................................... 67
`S.4.4
`Batch Analyses .......................................................................................................................................... 67
`S.4.5
`Justification of Specification...................................................................................................................... 70
`S.5
`Reference Standards or Materials ...................................................................................................76
`S.6
`Container Closure System...............................................................................................................77
`S.7
`Stability...........................................................................................................................................77
`S.7.1
`Stability Summary and Conclusions .......................................................................................................... 77
`S.7.2
`Postapproval Stability Protocol and Stability Commitment....................................................................... 81
`S 7.3
`Stability Data ............................................................................................................................................. 81
`A. Establishment Evaluation Report................................................................................................... 84
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`Reference ID: 2982868
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`Page 2 of 86
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`CMC Review #1
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`CMC REVIEW OF NDA 202-570
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`
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`III. List Of CMC Deficiencies Communicated and Resolved .......................................................85
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`Reference ID: 2982868
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`CMC REVIEW OF NDA 202-570
`CMC Review Data Sheet
`
`
`CMC Review Data Sheet
`
`
`
`1. NDA 202-570
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 01-Aug-2011
`
`4. REVIEWER: Debasis Ghosh, M. Pharm., Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`Original IND 73544 submission
`Original IND 73544 CMC review by Ying Wang
`CMC only pre-NDA meeting
`Pre-NDA Meeting Minutes
`
`
`
`6. SUBMISSION(S) BEING REVIEWED (CMC):
`
`
`Document Date
`12-Dec-2005
`10-Feb-2006
`29-Oct-2010
`12-Nov-2010
`
`Serial
`Number
`SR 002
`SR 021
`SR 026
`
`Submission(s) Reviewed
`Original NDA Submission
`Drug Product 9 month Stability
`Response to FDA Request for
`Information on 06-Jul-2011
`Labeling Amendment*
`Response to FDA Request for
`Information on 11-Jul-2011 and 12-Jul-
`2011*
`Follow up to Response to FDA Request
`for Information on 06-Jul-2011*
`Responses to queries received on July
`6,8, and 12, 2011
`Responses to queries received on July 25
`and 26, 2011
`Responses to queries received on July 25
`and 26, 2011
`*not reviewed by Drug Substance Reviewer
`
`SR 027
`
`SR 02