`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`202324Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`ONDQA Division Director’s Memo
`NDA 202-324, INLYTA (axitinib) Tablets 1mg and 5 mg
`Date: 25-JAN—2012
`
`Introduction
`
`INLYTA (axitinib) immediate release tablets (1 mg and 5 mg) are indicated for the
`treatment of advanced renal cell carcinoma. Dosing is twice daily with or without food.
`The maximum daily dose is 20 mg as, 10 mg twice daily
`
`This was a QbD application with a team CMC review process within ONDQA (drug
`substance, drug product, QbD, Biopharm, Analytical MODR, etc.) with consults for the
`QbD portions including Statictics. There were numerous late-cycle discussions with the
`applicant (see admin. section below).
`
`This is to be included in the action letter.
`
`(It) (4)
`
`This is a test the applicant ultimately agreed to adopt late in the review cycle and for
`which they did not have a validated method. Because this is a well known test with a
`long and well characterized history, ONDQA is comfortable allowing this time to for
`validation which should be straightforward.
`
`All other CMC-related deficiencies have been resolved for this application, and all
`related reviews are complete. There are no outstanding review deficiencies from the
`CMC standpoint.
`
`ONDQA recommends approval ofthis ADA.
`
`Administrative
`
`The original submission of this 505(b)(1) NDA was received 13-APR-2011 from Pfizer,
`Inc. The PDUFA date is l4-FEB-2012. Seven (7) CMC amendments were also
`reviewed during the review cycle, all of which were received in the last half of the review
`cycle; two of these within the past week. Most of the amendments were responses to
`earlier deficiency comments which required multiple cycles to resolve. In this regard, IR
`letters were sent, 26-SEP-2011, 02-DEC-2011, and l9-JAN-2012. Corresponding
`teleconferences on 05-DEC—2011, 20-DEC-2011, and l9-JAN—2012 were held with
`Pfizer to clarify deficiencies and discuss Pfizer’s counter-proposals and responses.
`
`Consults: EES acceptable on 04—DEC-2011, Biometrics complete lZ-DEC-201 l,
`PharmTox Satisfactory on 06-JAN-2012, Microbiology Satisfactory on 09-JAN-2012,
`DMEPA satisfactory on 19-JAN-2012.
`
`ONDQA Biopharm portion of the review completed today 25-JAN-2012 as an addendum
`to a previous approval recommendation.
`
`Reference ID: 3077225
`
`

`

`There is one CMC related PMC for this application. It provides for the applicant to
`validate testing for
`one within 90 (ninety) days.
`
`The NDA is supported by nine (9) drug master files (DMFs). All DMFs were assessed
`for adequacy in the respective chemistry reviews.
`
`0NDQA recommends approval ofthis NDA.
`
`Drug Substance (axitinib) (a neutral drug substance; NOT a salt or ester)
`Chemical Names:
`
`IUPAC: N—Methyl-Z-[3-((E)—2-pyridin—2-yl—vinyl)— lH—indazol-6—ylsulfanyl]-benzamide
`CAS: Benzamide,N-methyl—2-[[3-[(1E)-2-(2-pyridinyl)ethenyl]-lH-indazol-6-yl]thio]-
`Molecular Weight: 386.47 g/mol
`I Molecular Formula: C22H18N4OS
`Structure:
`
`
`
`The drug substance commercial process consists of
`
`M4)
`
`The sponsor has adopted a Quality by Des1gn (QbU) based approach tor drug substance
`development based on the principals of ICHQ8 and Q9 including multivariate
`experimental designs.
`
`The final drug substance axitinib is controlled by the acceptance criteria of quality
`attributes including identification, assay, impurities, and particle size and crystal form, to
`ensure the identity, strength, purity, and quality. Stability study with axitinib indicates
`that it is photo labile.
`(m4)
`
`0NDQA recommends approval ofthis NDA.
`
`Drug Product INLYTA (axitinib) immediate release tablets (1 mg and 5 mg)
`The drug product is an immediate release film coated tablet at two different strengths.
`The 1 mg tablet is red, oval, fihn coated, tablet de-bossed with “Pfizer” on one side and
`“l XNB” on the other. The 5 mg tablet is red, triangular, film coated tablet de-bossed
`with “Pfizer” on one side and “5 XNB” on the other.
`
`Reference ID: 3077225
`
`

`

`The inactive components of tablets are microcrystalline cellulose, lactose monohydrate,
`croscannellose sodium, magnesium stearate, and Opadry II red 32K15441 which consist
`of HPMC 2910, titanium dioxide, lactose monohydrate, glycerol triacetate and red iron
`oxide. All excipients are of compendial grade.
`
`The manufacturing process for the drug product involves
`
`W”
`
`The drug product is
`proposed to be marketed in 180 and 60 count HDPE bottles for the l and 5 mg strengths
`respectively.
`
`The applicant a submitted design space for the manufacturing process and for
`chromatographic analytical methods for the drug substance and the drug product. The
`applicant also requested corresponding flexibility for the analytical Method Operable
`Design Region (MODR) for these methods.
`
`The drug product is proposed to be marketed in 180 and 60 count HDPE bottles for both
`the 1mg and 5 mg strengths. Based on the stability data provided, the Agency grants a
`36 month expiry for both strengths packaged in these container closure systems.
`
`
`
`Thank you,
`
`Richard (Rik) Lostritto, Director, Division-I, ONDQA
`
`Reference ID: 3077225
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`01/25/2012
`
`Reference ID: 3077225
`
`

`

`
`
`NDA 202-324
`
`INLYTA (axitinib) tablets
`
`1 and 5 mg
`Pfizer, Inc.
`
`Drug Product Review
`Amit K. Mitra, Ph.D
`Branch II/ONDQA
`
`Division of Drug Oncology Products (Div 1)
`
`for
`
`Reference ID: 3076402
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`1. 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 or Not-Approval Recommendation ............................................................ 9
`
`III. Administrative........................................................................................................................... 9
`
`A. Reviewer’s Signature ........................................................................................................................ 9
`
`B. Endorsement Block........................................................................................................................... 9
`
`C. CC Block ........................................................................................................................................ 10
`
`Chemistry Assessment ........................................................................................... l 1
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ....... 11
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 .................................. 14
`
`A. Labeling & Package Inselt ............................................................................................................ 14
`
`111.
`
`List Of Deficiencies To Be Communicated ....................................................................... 19
`
`Reference ID: 3076402
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`. NDA 202-324
`
`. REVIEW #:2
`
`. REVIEW DATE: 22—JAN—2012
`
`. REVIEWER: Amit K. Mitra, Ph.D
`
`. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Original
`Amendment
`
`Amendment
`
`Amendment
`
`. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 3 1 Reviewed
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`. NAME & ADDRESS OF APPLICANT
`
`Document Date
`
`l3—APR—201 l
`
`21-OCT-201 1
`
`28-OCT-201 l
`
`01-NOV-201 1
`
`Document Date
`
`21-DEC-201 l
`
`05 -JAN-20 1 2
`
`1 8-JAN-20 1 2
`
`20-JAN-20 l 2
`
`Name:
`
`Address:
`
`Pfizer Inc.
`
`10646 Science Center Drive, San Diego, CA
`92121
`
`Reference ID: 3076402
`
`Page 3 of 19
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Representative:
`
`Telephone:
`
`Alison Russell, Ph.D
`
`(858)—344-4473
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Inlyta
`b) Non-Proprietary Name (USAN): Axitinib
`c) Code Name/# (ONDC only): AG-013736
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 1
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b)(1)
`
`10. PHARMACOL. CATEGORY: Advanced Renal Cell Carcinoma
`
`11. DOSAGE FORM:
`
`Tablets
`
`12. STRENGTH/POTENCY:
`
`1 and 5 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:
`
`Reference ID: 3076402
`
`Page 4 of 19
`
`

`

`.
`
`;
`
`.
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`_
`
`; 5
`
`
`
`N-Methyl-Z-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide
`
`CaHquos. 386.47.
`
`17- RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DATE
`
`1
`
`STATUS
`
`Idem “BED/20“ -'KDIMill'a
`
`
`
`07/07/2010
`
`Adequate
`, by Dr.
`C.
`
`Strassing
`
`Reference ID: 3076402
`
`Page 5 of 19
`
`

`

`
`
`(b) (4)
`
`
`
`HI
`
`H1
`
`III
`
`Chemistry Review Data Sheet
`
`(I!)(4)
`
`Adequate
`. by Dr.
`G. Lunn
`
`The applicant is not
`proposing to use this
`package for
`commercialization
`
`
`
`
`
`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 Documents:
`
`
`
`18. STATUS:
`
`ONDC:
`
`CONSULTS/ CMC
`
`Reference ID: 3076402
`
`Page 6 of 19
`
`

`

`
`
`Chemistry Review Data Sheet
`
`————
`04-DEC-2011 Mr. M. Stock
`
`————
`Satisfactory. However,
`12-DEC—2012 Dr. K. Riviere
`the reviewer is in the
`
`process of writing a
`second review. The final
`
`review will be in the
`
`Darrts by Friday,
`1/27/2012.
`
`Not requested since the
`application pre—dates the
`IQP for methods
`validation
`
`Methods Validation
`
`
` -_———
`
`OPDRA ———
`09-DEC-2011 Dr. A. K. Mitra
`
`09-JAN-2012 Dr. D. A. Miller
`
`OGD'
`
`CONSULTS/ CMC
`
`RELATED
`
`REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`—_———
`————
`Methods Validation ———
`
`-————
`————
`-_———
`
`19. ORDER OF REVIEW (OGD Only)
`
`The application submission(s) covered by this review was taken in the date order of
`receipt.
`Yes
`No
`If no, explain reason(s) below:
`
`Reference ID: 3076402
`
`Page 7 0f 19
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NBA 202-324
`
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`The application is recommended for approval with respect to CMC.
`
`Include the following language in the action letter:
`Based on the provided stability data, an expiration dating period of 36 months is granted
`for the drug product when stored at 20-25°C (68-77°F); excursions permitted between
`15°C and 30°C (59°F and 86°F).
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`None
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`The proposed commercial axitinib drug product is an immediate release fihn coated
`tablet at two different strengths. The 1 mg tablet is red, oval, fihn coated, tablet de-
`bossed with “Pfizer” on one side and “l XNB” on the other. The 5 mg tablet is red,
`triangular, fihn coated tablet de-bossed with “Pfizer” on one side and “5 XNB” on the
`other. The inactive components of tablets are microcrystalline cellulose, lactose
`monohydrate, croscarmellose sodium, magnesium stearate, and Opadry H red
`32K15441 which consist of HPMC 2910, titanium dioxide, lactose monohydrate,
`glycerol triacetate and red iron oxide. All excipients are of compendial grade. An
`Information Request was sent to the applicant on the flmctional attributes of the
`excipients and their impact of drug product performance. The applicant’s response is
`satisfactory according to the current regulatory standard. The manufacturing process
`for the drug product involves
`(we)
`
`The drug product is proposed to
`be marketed in 180 and 60 count I-IDPE bottles for the l and 5 mg strengths
`respectively.
`
`Axitinib has been formulated in several orally administered dosage forms
`and an intravenous (IV) solution during
`different phases of clinical development. The tablets used in early clinical trials were
`manufactured
`(m4)
`
`(we)
`
`The proposed
`
`Reference ID: 3076402
`
`Page 8 of 19
`
`

`

`
`
`Executive Summary Section
`
`commercial formulation is manufactured
`
`«0(4)
`
`The drug product was
`developed using some elements of Quality by Design elements such as design of
`experiments, thermodynamic modeling and risk assessment. However, a complete
`linkage of raw material attributes and process parameters to product quality was not
`achieved. For example dissolution rate was not monitored during design space
`evaluation. The proposed commercial manufacturing process is different from the
`clinical supplies and the registration stability batches
`
`(am)
`
`The proposed
`commercial batch size is proposed to be lower than that of the primary registration
`batches. Several Information Requests were sent to the applicant Via several
`Information Request letters by the ONDQA project manager. The final response
`provided by the applicant (21-DEC-2011) is satisfactory to the reviewer.
`
`For the Drug Substance summary and review see the review by Dr. J. Tang, Dated
`20-JAN-2012.
`
`B. Description of How the Drug Product is Intended to be Used
`The drug product is proposed to be marketed in 180 and 60 counts HDPE bottles in l
`and 5 mg strengths respectively. The recommended starting oral dose of INLYTA is 5
`mg twice daily. INLYTA may be taken with or without food. The maximum daily dose
`is recommended to be 10 mg twice daily.
`
`The applicant has provided sufficient stability data for a 36 months tentative shelf life
`under long term storage conditions.
`
`C. Basis for Approvability or Not-Approval Recommendation
`The applicant has responded to the latest Information Request letter satisfactorily.
`Therefore, the application may be approved.
`
`1H. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`ChemistName/Date: Same date as draft review
`
`ChemistryTeamLeaderName/Date
`ProjectManagerName/Date
`
`Reference ID: 3076402
`
`Page 9 of 19
`
`

`

`Q
`
`‘
`
`CHEMISTRY REVIEW
`
`_
`
`; 5
`
`Executive Summary Section
`
`C. CC Block
`
`
`
`Reference ID: 3076402
`
`Page 10 of 19
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMIT K MITRA
`01/24/2012
`
`SARAH P MIKSINSKI
`01/24/2012
`
`Reference ID: 3076402
`
`

`

`
`
`NDA 202324
`
`InlytaTM
`(Axitinib) Tablets
`1 mg and 5 mg
`
`Pfizer, Inc.
`
`Z. Jean Tang, Ph.D
`Division of New Drug Quality Assessment I
`Branch III
`
`CMC REVIEW OF NDA 202324 DRUG SUBSTANCE
`
`For the Division of Drug Oncology Products (HFD-lSO)
`
`Reference ID: 3076338
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`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 Chemistry Assessments......................................................................................... 7
`
`A. Description of the Drug Product(s) and Drug Substancc(s) ............................................................. 7
`
`B. Description of How the Drug Product is Intended to be Used.......................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 8
`
`III. Administrative........................................................................................................................... 8
`
`A. Reviewer’s Signature ........................................................................................................................ 8
`
`B. Endorsement Block........................................................................................................................... 8
`
`C. CC Block .......................................................................................................................................... 8
`
`Chemistry Assessment ...............................................Error! Bookmark not defined.
`
`III.
`
`List Of Deficiencies To Be Communicated ......................................................................... 9
`
`Reference ID: 3076338
`
`

`

`'“gnr
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`.2253
`
`CMC Review Data Sheet
`
`1. NDA 202—324
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: 20-Jan-2012
`
`4. REVIEWER: Z. Jean Tang, Ph.D.
`
`5. PREVIOUS DOCUlVIENTS:
`
`Previous Documents
`
`Document Date
`
`Original IND 63662 Submission
`Original IND CMC review by
`CMC only pre—NDA meeting
`
`13-NOV-2001
`William C TimmeOl-AUG-2008
`
`6. SUBMISSION(S) BEING REVIEWED (CMC):
`
`0023
`
`0027
`
`21-Dec-2011
`
`22-Dec-2011
`
`20-Jan-2012
`
`20-Jan-2012
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Pfizer Inc
`
`Address:
`
`10646 Science Center Drive
`
`San Diego, CA 92121
`
`Representative: Alison Russell, Worldwide Regulatory Strategy
`
`Telephone:
`
`(858)622-3234
`
`Reference ID: 3076338
`
`Page 3 of 22
`
`

`

`
`
`Chemistry Review Data Sheet
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: INLYTETM
`b) Non-Proprietary Name: Axitinib
`c) Code Name/# (ONDQA only): NA
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 1 New Molecular Entity
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY: Anti-cancer
`
`11. DOSAGE FORM:
`
`tablets
`
`12. STRENGTH/POTENCY:
`
`1 mg and 5 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`l4. 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:
`
`Reference ID: 3076338
`
`Page 4 of 22
`
`

`

`
`
`Chemical Name:
`
`IUPAC : N-Methyl-Z-[3-((E)-2-pyridin-2-yl-vinyl)- lH-indazol-6-ylsulfanyl]-benzamide
`CAS: Benzamide, N—methyl—Z—[[3—[(lE)—2-(2—pyn'dinyl)ethenyl]—lH—indazol—6—yl]thio]—
`JAN: N—Methyl—2-( {3—[(1E)-2-(pyridin—2-yl)ethen- l -yl]- 1H-indazol—6—yl} sulfanyl)benzamide
`
`Molecular Formula: C22H13N4OS
`
`Molecular Weight: 386.47 g/mol
`
`l7. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`No DMF for drug substance.
`
`B. Other Documents:
`
`NlA
`
`Reference ID: 3076338
`
`Page 5 of 22
`
`

`

`
`
`Chemistry Review Data Sheet
`
`18. STATUS:
`
`0NDQA:
`CONSULTS/ CMC
`
`RELATED
`
`REVIEWS
`
`Biostatistic
`
`RECOMMENDATION
`
`DATE
`
`Not Recommended for
`Design Spacemfgf
`
`12—DEC-2011
`
`Meiyu Shen
`
`EES
`
`Satisfactory
`
`04—DEC-2011
`
`Shawn Gould & Michele Perry
`Williams
`
`Dru- Substance
`
`Satisfacto
`
`23-JAN—2012
`
`Jean Zhe Tan
`
`
`
`Pharm/Tox
`
`LNC
`
`Methods Validation
`
`N/A, according to the
`cuiTent 0ND O A olic
`
`23-JAN-2011
`
`12—DEC-2011
`
`Donn o obert Liu
`
`06-JAN-2012
`
`MA Goheer
`
`12-DEC-2011
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`DMEPA*
`
`EA
`
`0 Initial Review
`0 Final Review:
`
`Satisfacto
`
`0 08-NOV-2011 Denise V. Baugh
`0 l9-JAN—2012
`
`09—DEC-2011
`
`AmitMitra
`
`Microbiolo
`
`12-JAN-2012
`
`Denise Miller
`
`Reference ID: 3076338
`
`Page 6 of 22
`
`

`

`
`
`Executive Sulmnary Section
`
`The Chemistry Review for NBA 202-324
`
`The Executive Summon
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`The application is recommended for APPROVAL with respect to CMC
`
`Include the following language in the action letter:
`Based on the provided stability data, an expiration datingperiod of36 months is granted
`for the drug product when stored at 20-25°C (68-77°F); excursions permitted between
`15°C and 30°C (59°F and 86°F).
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`The method and method validation data used to detect
`
`(m4) and
`
`GM)
`
`level in Drug Substance will be provided post-approval.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Axitinib (compound number: AG-013736), a substituted indazole achiral derivative
`with a trans configlu‘ation at the olefmic double bond , is an oral, potent, and selective
`tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGF)
`receptors -1, -2, and -3. Axitinib is a white to light yellow powder, and the solubility of
`axitinib was higher in low pH media (> 1800 ua/ml at DH 1.1) but decreases rapile
`across the pH range (0.2 112/1111 at pH 7.8).
`one
`
`Its stmcture was eluc1dated by IR,
`l-lNMR, CNMR, MS, UV/Vis, optical rotation and X—ray crystallography.
`
`The proposed drug substance commercial process consists of
`
`(M4)
`
`The sponsor has adopted a Quality by Desrgn (QbD) based approach
`for dnlg substance development based on the principals of ICHQ8 and Q9.
`
`The final drug substance axitinib is controlled by the acceptance criteria of quality
`attributes including identification, assay, implu‘ities, and paiticle size and c1ystal form,
`to ensm‘e the identity, strength, pluitv. and qualitv. Stabilitv studV with axitinib
`indicates that it is photo labile.
`
`(no)
`
`Reference ID: 3076338
`
`Page 7 of 22
`
`

`

`
`
`Executive Summary Section
`
`For the Drug Product summary and review see the review by Dr. Amit Mitra, dated 24-
`JAN—2012.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Please refer to Dr. Amit Mitra’s Review of Drug Product, dated 24-JAN—2012.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The applicant has responded to the latest Information Request letter satisfactorily.
`Therefore, the application may be approved.
`
`III. Administrative
`
`A. Reviewer’s Signature
`(See appended electronic signature page)
`
`Z. Jean Tang, PhD.
`CMC Reviewer
`
`Branch 1]], Division I, ONDQA
`CDER, FDA
`
`B. Endorsement Block
`
`(See appended electronic signature page)
`
`Sarah Pope Miksinski, Ph.D.
`Branch Chief
`
`Branch H, Division I, ONDQA
`CDER, FDA
`
`C. CC Block entered electronically in DARRTS
`
`14 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 3076338
`
`Page 8 of 22
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ZHE J TANG
`01/24/2012
`
`SARAH P MIKSINSKI
`01/24/2012
`
`Reference ID: 3076338
`
`

`

`
`
`
`
`
`Axitinib
`Tablet
`1 mg and 5 mg
`
`
`Pfizer Inc.
`
`
`
`
`
`
`CMC Reviewer
`(Analytical sections)
`
`Donghao (Robert) Lu, Ph.D.
`
`Division I of Pre-Marketing Assessment
`Office of New Drug Quality Assessment
`
`
`
`
`
`
`Overall Recommendation: The development and validation results for the analytical
`sections involved in this NDA are acceptable.
`
`Reference ID: 3057087
`
`

`

`
`
`Chemistry Assessment Section
`
`8.4 Control of Drug Substance (Analytical Methods)
`
`8.4.] Specification (for reference)
`
`
`
`Reference ID: 3057087
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DONGHAO R LU
`12/12/2011
`
`SARAH P MIKSINSKI
`12/12/2011
`
`Reference ID: 3057087
`
`

`

`
`
`NDA 202-324
`
`INLYTA (axitinib) tablets
`
`1 and 5 mg
`Pfizer, Inc.
`
`Drug Product Review
`Amit K. Mitra, Ph.D
`Branch II/ONDQA
`
`Division of Drug Oncology Products (Div 1)
`
`for
`
`Reference ID: 3056759
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`1. 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 or Not-Approval Recommendation ............................................................ 9
`
`III. Administrative......................................................................................................................... 10
`
`A. Reviewer’s Signature ...................................................................................................................... 10
`
`B. Endorsement Block......................................................................................................................... 10
`
`C. CC Block ........................................................................................................................................ 10
`
`Chemistry Assessment ........................................................................................... l 1
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ....... 11
`
`S DRUG SUBSTANCE [Name Manufacturer] .............................................................................. 11
`
`P DRUG PRODUCT [Name Dosage form] .................................................................................... 11
`
`A APPENDICES .............................................................................................................................. 57
`
`R REGIONAL INFORMATION ..................................................................................................... 57
`
`II. Review Of Common Technical Document-Quality (Ctd—Q) Module 1 ..................................60
`
`A. Labeling & Package Insert ............................................................................................................ 60
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................... 61
`
`III.
`
`List Of Deficiencies To Be Communicated ....................................................................... 64
`
`Reference ID: 3056759
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 202-324
`
`2. REVIEW #:1
`
`3. REVIEW DATE: 09—DEC—2011
`
`4. REVIEWER: Amit K. Mitra, Ph.D
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission 3 Reviewed
`
`'
`'
`Original
`Amendment
`
`Amendment
`
`Amendment
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`l3-APR—201 1
`
`21-OCT-2011
`
`28-OCT-201 1
`
`01-Nov-2011
`
`Name:
`
`Address:
`
`10646 Sc1ence Center Drive, San Diego, CA
`92 12 1
`
`Pfizer Inc.
`
`Reference ID: 3056759
`
`Page 3 of 65
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Representative:
`
`Telephone:
`
`Alison Russell, Ph.D
`
`(858)—344-4473
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Inlyta
`b) Non-Proprietary Name (USAN): Axitinib
`c) Code Name/# (ONDC only): AG-013736
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 1
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`10. PHARMACOL. CATEGORY: 505 (b)(1)
`
`11. DOSAGE FORM:
`
`Tablets
`
`12. STRENGTH/POTENCY:
`
`1 and 5 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:
`
`Reference ID: 3056759
`
`Page 4 of 65
`
`

`

`.
`
`;
`
`.
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`_
`
`; 5
`
`
`
`N-Methyl-Z-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide
`
`CaHquos. 386.47.
`
`17- RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DATE
`
`1
`
`STATUS
`
`
`
`'Adequat--K.DIMilra
`
`
`
`07/07/2010
`
`Adequate
`, by Dr.
`C.
`
`Strassing
`
`Reference ID: 3056759
`
`Page 5 of 65
`
`

`

`
`
`Chemistry Review Data Sheet
`
`(5) (4)—
`HI
`
`(5) (4)
`
`3
`
`Adequate
`. by Dr.
`
`HI
`
`IE
`
`HI
`
`7
`
`4
`
`The applicant is not
`proposing to use this
`package for
`commercialization
`
`4
`
`IAction 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 Documents:
`
`
`
`18. STATUS:
`
`ONDC:
`
`CONSULTS/ CMC
`
`Reference ID: 3056759
`
`Page 6 of 65
`
`

`

`
`
`Chemistry Review Data Sheet
`
`————
`
`————
`-'—-_——
`————
`————
`————
`09-DEC-2011
`
`—--_——
`
`
` -_———
`
`OGD'
`
`CONSULTS/ CMC
`
`RELATED
`
`REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`_'_———
`————
`Methods Validation ———
`
`-————
`
`EA
`
`Radio nharmaceutical
`
`19. ORDER OF REVIEW (OGD Only)
`
`The application submission(s) covered by this review was taken in the date order of
`receipt.
`Yes
`No
`If no, explain reason(s) below:
`
`Reference ID: 3056759
`
`Page 7 0f 65
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NBA 22-088
`
`The Executive Summam
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`The application is approvable pending resolution of several CMC issues provided in the
`“Basis for Approvability or Not-Approval Recommendation” section.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`H. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`The proposed commercial axitinib drug product is an immediate release fihn coated
`tablet at two different strengths. The 1 mg tablet is red, oval, film coated, tablet de-
`bossed with “Pfizer” on one side and “l XNB” on the other. The 5 mg tablet is red,
`triangular, fihn coated tablet de-bossed with “Pfizer” on one side and “5 XNB” on the
`other. The inactive components of tablets are microcrystalline cellulose, lactose
`monohydrate, croscarmellose sodium, magnesium stearate,