`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
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`APPLICATION NUMBER:
`203085Orig1s000
`
`CHEMISTRY REVIEW(S)
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`METHODS VALIDATION REPORT SUMMARY
`
`TO:
`
`
`
`
`Donghao Lu/Josephine M Jee, CMC Reviewer
`Office of New Drug Quality Assessment (ONDQA)
`E-mail Address: donghao.lu@fda.hhs.gov
`Phone: (301)-796-2059
`Fax:
`(301)-796-9747
`
`FROM: FDA
`
`Division of Pharmaceutical Analysis
`Michael Trehy, MVP Coordinator
`Suite 1002
`1114 Market Street
`St. Louis, MO 63101
`Phone: (314) 539-3815
`
`
`
`
`Through: Benjamin J. Westenberger, Deputy Director
` Phone: (314) 539-3869
`
`SUBJECT: Methods Validation Report Summary
`
`
`
`Application Number: 203085
`
`
`
`
`Name of Product: STIVARGA® (Regorafenib) Tablets, 40 mg
`Applicant: Bayer Healthcare Pharmaceuticals, Inc.
`Applicant’s Contact Person: Philip Johnson, Deputy Director, Global Regulatory Affairs
`Address: P.O. Box 1000 Montville, NJ 07045-1000
`
`
`
`
`
`
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`Date Methods Validation Consult Request Form Received by DPA: 6/7/12
`Date Methods Validation Package Received by DPA: 6/7/12
`
`Date Samples Received by DPA: 7/5/12
`Date Analytical Completed by DPA: 9/14/12
`
`Laboratory Classification: 1. Methods are acceptable for control and regulatory purposes.
`
`2. Methods are acceptable with modifications (as stated in accompanying report).
`
`3. Methods are unacceptable for regulatory purposes.
`
`
`
`Comments: Analyst’s comments are attached.
`
`Telephone: (973) 487-2181
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`Fax: (973) 487-2016
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`Reference ID: 3192712
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`Page 1 of 3
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`Version: 7/13/2011
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
`Food and Drug Administration
`
`
`
`
`
`
`for Drug Evaluation and Research
`Center
`
`
`
`
`
` Division of Pharmaceutical Analysis
`St. Louis, MO 63101
`Tel. (314) 539-3897
`
`
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`
`
`September 20, 2012
`
`
`
`Donghao Lu, CDER, ONDQA, CMC Reviewer
`Josephine M Jee, CDER, ONDQA, CMC Reviewer
`
`B. J. Westenberger, Deputy Director, Division of Pharmaceutical Analysis
`
`Wei Ye, Chemist
`
`Method Validation for NDA 203085
`STIVARGA® (Regorafenib) Tablets, 40 mg
`Bayer HealthCare Pharmaceutics Inc.
`
`
`Date:
`
`To:
`
`
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` Through:
`
`From:
`
`Subject:
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`The following methods were valuated and are acceptable for quality control and regulatory purposes:
`
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`1.
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`(Bayer Healthcare Pharmaceuticals Inc., Test Procedure S.4.2.01-02, Method A, Page 8 of 21)
`
`2. Assay IDs & Impurities
`(Bayer Healthcare Pharmaceuticals Inc., Test Procedure S.4.2.01-02, Method B, Page 13 of
`21)
`
`3. Assay & Impurities (HPLC1)
`(Bayer Healthcare Pharmaceuticals Inc., Test Procedure P.5.2.01-03, Page 23 of 37)
`
`
`
`
`The Division of Pharmaceutical Analysis (DPA) has the following comments pertaining to this method.
`
`1. Assay & Impurities (HPLC1)
`(Bayer Healthcare Pharmaceuticals Inc., Test Procedure P.5.2.01-03, Page 23 of 37)
`
`
`• On page 28, Section f) Linearity, a calculation formula needs to be given for clarification.
`
`• On page 32, Section Calculation for assay of regorafenib, the formula of dilution factor
`should be change to
`f = 100 mL · 50 mL = 1250 mL instead of
` 4 mL
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`Page 2 of 3
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`Version: 7/13/2011
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`Reference ID: 3192712
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`(b) (4)
`
`(b) (4)
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`1 Page(s) has been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MICHAEL L TREHY
`09/21/2012
`
`BENJAMIN J WESTENBERGER
`09/21/2012
`
`Reference ID: 3192712
`
`

`

`
`
`ONDQA Division Director’s Memo (updated)
`NDA 203-085, STIVARGA (regorafenib) Tablets, 40 mg
`Date: 14-SEP-2012
`
`Reference is made to the 06-SEP-2012 Division Director’s Memorandum for this application. All
`case details can be located in that memorandum. The previous memorandum states that all CMC
`review deficiencies have been resolved for this application, and all related reviews are complete.
`An overall acceptable recommendation from the Office of Compliance was issued for this
`application on 05-SEP-2012.
`
`Reference is also made to the Chemistry Reviewer’s 14-SEP-2012 update, which provides
`technical clarification regarding some of the resolved chemistry review issues. The 14-SEP-2012
`memorandum also clarifies a discrepancy in the initial 30-AUG-2012 review, which confirmed an
`expiration dating period of
` The 14-SEP-2012 updates this confirmation by stating
`that the Applicant requested a 36 month shelf-life, which is granted based on their provided
`stability data. Additionally, the CMC reviewer’s update states that the carton and container labels
`submitted on 11-SEP-2012 were found to be acceptable from a CMC standpoint.
`
`There is no change to the previous ONDQA recommendation: all CMC review issues have
`been resolved, and ONDQA recommends approval of this NDA pending the submission of
`acceptable PI labeling. Due to the Agency’s agreement with the Applicant’s proposed
`expiration dating period of 36 months, no confirmatory language is needed in the approval
`letter when issued.
`
`
`Reference ID: 3189422
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`09/14/2012
`
`Reference ID: 3189422
`
`

`

`CHEMISTRY REVIEWER MEMORANDUM
`
`To:
`
`From:
`Thru:
`Date:
`
`NDA 203085
`
`Josephine Jee., CMC Reviewer, ONDQA
`Nallaperumal Chidambaram, Ph.D., Acting Chief, Branch 11
`12-SEP-2012
`
`Drug:
`Route of administration:
`
`Stivargam(regorafenib)
`Tablet
`
`Strength:
`
`Subj ect:
`
`40 mg
`
`UPDATES
`
`Note: I requested Liang Zhou to place my review in DARRTS on my behalf as I was going on leave
`during that time. I inadvertently forwarded an earlier version of my CMC-DP review for NDA 203085 to
`Liang Zhou. and the same was placed into DARRTS during my absence. The purpose of this
`Memorandum is to clarify some points that are missing in the uploaded version in DARRTS.
`
`Background
`NDA 203085 was submitted on 27-APR—2012 and filed under expedited priority review
`category. The CMC—DP review was completed on 27-AUG-2012 (GRMP date 30-AUG-2012).
`Since the applicant
`(”(4)
`
`in the manufacturing process of the drug product.
`During the Mid-Cycle of NDA 203085 (July 26, 2012), I conveyed my concerns to the Team and
`requested to send an IR to Bayer with the following comments:
`
`1. Provide appropriate test(s) to confirm
`
`M“)
`
`2. Provide controls. including data, to limit the exposure to the conditions which cause
`"M" critical to assuring the quality and efficacy of this
`
`product.
`
`“M" Include
`3. Provide a drug product
`(no) residual solvents. heavy metals, impurities, assay, residue on
`appearance, identification.
`ignition, physical form. particle size distribution. and bulk density.
`
`(m4) is maintained throughout the shelf-life
`4. Provide analytical data to demonstrate that the
`of Regorafenib Tablets. This test and the corresponding acceptance criterion should be included in the
`specification for Regorafenib Tablets.
`
`The above comments were not forwarded to Bayer until 07—AUG-2012. Bayer responded to
`these comments on 13-AUG-2012. Bayer indicated that the assurance of the
`(m4) is
`M“)
`determined by Dissolution testing as a surrogate for the content of the
`in the tablets. In addition, Bayer indicated that they were lmable to perform m4)
`because they
`am";
`therefore, they stated there will be too much interference. However, at the 15—AUG—2012
`
`Reference ID: 31 89229
`
`

`

`Teleconference with ONDQA, Bayer stated that they have performed mar I requested that
`they send their
`M“) to us. Bayer submitted these
`mm) on the 24-
`AUG—2012 Amendment.
`mm for Regorafenib
`The
`ma) sent represented the
`Tablets, Batch No. BX035FA after 6 months storage at 6°C and 40°C/75% RH; and 18 months
`at 25°C/60% RH; and after 24 months at 30°C/75% RH.
`Comment: The analytical method for this
`mm was not validated as stated by Bayer and
`Bayer committed to validate this post-approval. The
`mm can only serve as a
`baseline for any changes in the Regorafenib Tablets for that particular batch.
`
`(b)(4)
`I discussed the use of dissolution testing as a surrogate for the
`with the Biopharm reviewers, Dr. S. Suarez, and Dr. E. Chikhale, on 14-AUG-2012. They told
`me that there were previous ap roved NDAs using Dissolution testing as a surrogate for the
`content of the
`m however, FDA recommends in this case tightening the
`acceptance criteria for the Dissolution testing. On 15-AUG-2012, FDA (R. Lostritto, S. Suarez,
`E. Chikhale, and J.Jee) discussed this issue with Bayer representatives. FDA recommended that
`in order to control the
`(m4) of Regorafenib Tablets, Bayer should tighten their
`Dissolution acceptance criteria to a more stringent one: Q M“) at t=30 min. with stage testing
`according to USP, EP, and JP.
`m“): dissolution after 45 min. with not less than (m4)
`The testing for absence of
`(mean of 6 individual samples) without stage testing. If the mean dissolution rate of m(4) is not
`met, then
`(m4) testing is required to confirm that not more than M“) of
`(hm) are
`present in the tablets
`M“) testing methodology and specifications would not be implemented
`until it is submitted to FDA for approval).
`
`Bayer sent an email dated 16—AUG—2012 a made the wrong citation in my review indicating this
`communication came from FDA, see pages 15, 16, and 33 of my CMC—DP review in DARRTS)
`and the part of the communication content is as shown below:
`
`In order to control the
`
`(m4)
`
`content of Regorafenib Tablets, Bayer and FDA
`
`agreed on the following:
`Tightening of the dissolution specifications
`a) For QC testing: Q= :2}, t=30 min with stage testing acc. to USP, EP, JP
`b) Testing for absence of
`mu) dissolution after 45 min with not less than
`(mean of 6 individual samples) and without stage testing
`c) If mean dissolution rate of (m4) is not met, then
`mmtesting is required confirming that
`not more than (m4) of
`M“) are present in the tablets
`(hm) testing
`methodology & specifications would not be implemented until submitted to FDA post-
`approval)
`
`(5) (4)
`
`Following the 16-AUG-2012 email, Bayer submitted an Amendment dated 24-AUG-2012
`containing the information below.
`as an attribute
`I Updated specification (at release and at shelf-life) without
`focusing on the revised dissolution testing as discussed in the 15-AUG-2012
`Teleconference.
`
`0') (4)
`
`. Updated stability protocol.
`
`Reference ID: 31 89229
`
`

`

`I Dissolution Test Procedure.
`
`(ll) (4)
`
`container, Batch
`I Update Stability data, including stability data for the
`T145A01 at storage conditions: 25°C/60% RH (18 months); 30°C/75% RH (18
`months), 40°C/75% RH (6 Months).
`
`0n 04—SEP-2012, I discussed with E. Chikhale, Biopharm Reviewer concerning the m4)
`amount allowed as stated by Bayer and quoted in J.Jee’s Review. Dr. Chikhale stated
`that this amount is unacceptable. However, I indicated to her that the representatives of FDA
`have not made any comments to Bayer in their communications concerning the
`(mo
`in DP(15—AUG—2012 Teleconference and in Bayer’s subsequent communications; 16—AUG—2012
`email and 24-AUG-2012 Amendment).
`
`At the end of this discussion, the Agency decided to send the following clarification via email to
`Bayer on 07-Sep-2012; see text below:
`
`mm was not agreed upon dming
`“Please note that the acceptance criterion for the
`”min the drug
`the teleconference on 8/l 5/12, and that your suggested
`product will be a review issue when validated
`0"“) information (including justification for the proposed
`acceptance criterion) is submitted.”
`
`Bayer acknowledged on 07-SEP-2012: “We acknowledge FDA's comment that this proposed
`specification would be a review issue during the review of the
`(m4) method (to be submitted
`post-approval). Can you please confirm that there are no current review issues with regards to
`the updated dissolution specifications Bayer submitted in order to control the
`(m4)
`“(4) in the drug product?”
`
`FDA confirmed to Bayer on 10—SEP-2012 that there are no current review issues with regards to
`the updated dissolution specifications Bayer submitted.
`
`The uploaded version of my review in DARRTS did not clearly state the amount of shelf-life that
`was granted for Regorafenib Tablets. Dr. Liang Zhou recommended to grant
`mm) of shelf-
`life based on 18 months of long-tenn stability data in
`ma) bottles. Bayer had submitted
`24 months of real time data (25°C/60% RH and 30°C/75 % RH) and 6 months at accelerated
`(“3
`conditions (40°C/75% RH) for 3 primary stability batches packed in proposed package sizes:
`; and 18 months of real time data (25°C/60% RH and 30°C/75 %
`RH) and 6 months at accelerated conditions (40°C/75% RH) for the
`(m4) bottles.
`Bayer requested 36 months shelf-life, which was granted based on their stability data; see
`ICH QlE (When long-term data show little or no change and little variability, extrapolation of
`the shelf-life beyond the period covered by long-term data can be proposed. The proposed shelf—
`life can be up to twice as long as, but should not be more than 12 months beyond, the period
`covered by long-term data can be proposed).
`
`The carton and container labels are found acceptable by CMC and DMEPA on ll-SEP—2012.
`DIVIEPA has pending labeling issues and will be communicated to Bayer soon.
`
`We await method validation testing from the Division of Pharmaceutical Analysis (DPA) in St.
`Louis.
`
`Reference ID: 31 89229
`
`

`

`M“) and specification will be
`Also, the method validation for the
`provided by Bayer at post-approval (Bayer committed to this; see Amendment dated 24-AUG-
`2012).
`
`An overall acceptable recommendation for the manufacturing facilities dated 05-SEP-2012 was
`received from the Office of Compliance for NBA 203085 (see attached EES report).
`
`Appllcauon:
`Olg. Code:
`Priomv:
`Stamp Date:
`PDUFA Date:
`Action Goal:
`Dlstrlcl Goal:
`
`NDA 203085/000
`107
`1
`27*APR72012
`27-OCT~2012
`
`FDA contacts:
`
`J. MARTIN
`L ZHOU
`
`Ovemll Recommendation:
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`Sponsor:
`
`BAYER HLTHCARE
`340 CHANGEBRIDGE RD
`PINE BROOK. NJ 07058
`Stwama
`
`Brand Name:
`Estab. Name:
`Gan-tic Nam-2
`Product Number; Dosage Form: lngrodlonl: suonglhc
`001; TABLET: REGORAFENIB: 40M6
`
`Project Manager
`Team Leader
`
`(HFV’530)
`
`301 7962072
`301 796 I781
`
`ACCEPTABLE
`PENDING
`
`on OS-SEP-2012
`on 01 -MA.V-2012
`
`by 0 SMITH
`by EES_PROD
`
`(HFD-323)
`
`3017965321
`
`Establlsnmont:
`
`CFN:
`
`a)“,
`
`FEI:
`
`D)“,
`II!) (4)
`
`DMF No:
`Responsibilities:
`promo:
`Lost Milestone:
`Milestone Date:
`Doclslon:
`Reason:
`
`Establishment:
`
`DMF No:
`Responslbllltlos:
`Profile:
`Last lam-stone:
`Milestone Dale:
`Decision:
`Reason:
`
`AADA:
`
`OAI Slalus:
`
`NONE
`
`3002806462
`
`AADA:
`
`OAI Status:
`
`NONE
`
`FINISHED DOSAGE PACKAGER
`TABLETS. PROMPT RELEASE
`0C RECOMMENDATION
`03—MAY—20 I 2
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`FEI:
`9610135
`CFN:
`BAYER SCHERING PHARMA AG
`CHEMPARK
`LEVERKUSEN, , GERMANY
`
`FINISHED DOSAGE MANUFACTURER
`TABLETS, PROMPT RELEASE
`OC RECOMMENDATION
`05-3EP2012
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`September 13. 2012 3:37 PM
`
`FDA Confidential - Internal Distribution Only
`
`Page 1 of 2
`
`Reference ID: 31 89229
`
`

`

`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Esmbisllmenl:
`
`CFN:
`
`$10496
`
`FEI:
`
`“3229486
`
`DMF No:
`
`BAYER SCHERNG PHARMA AG
`217-333 FRIEDRICH—EBERT STRASSE
`
`WUPPERTAL-ELBERFELD, . GERMANY
`
`AADA:
`
`Responsiillllles:
`
`DRUG SUBSTANCE MANUFACTURER
`
`Last Milestone:
`
`Milestone Dale:
`
`Decision:
`
`Reason:
`
`OC RECOMMBIDATION
`
`02-MAY-2012
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`Eslnbislunenl:
`
`CFN:
`
`FEI:
`
`DNF No:
`
`MDA:
`
`Responsibilities:
`
`FINISHED DOSAGE PACKAGER
`
`Profile:
`
`TABLETS, PROMPT RELEASE
`
`OAI Status:
`
`NONE
`
`Last Milestone:
`
`Ililutone Dole:
`
`Decision:
`
`Reason:
`
`0C RECOMMENDATION
`
`os-mv-zmz
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Reference ID: 3189229
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOSEPHINE M JEE
`09/14/2012
`Memorandum to clarify the shelf-life of Regorafenib Tablets, EES updates, and Labeling updates.
`
`NALLAPERUM CHIDAMBARAM
`09/14/2012
`I concur
`
`Reference ID: 3189229
`
`

`

`
`
`ONDQA Division Director’s Memo
`NDA 203-085, STIVARGA (regorafenib) Tablets, 40 mg
`Date: 06-SEP-2012
`
`Introduction
`STIVARGA (regorafenib) Tablets are formulated as light pink, oval-shaped film-coated tablets
`debossed with “BAYER” on one side and with “40” on the other. Each tablet contains 40 mg of
`regorafenib
` and the following inactive ingredients: microcrystalline cellulose,
`croscarmellose sodium, magnesium stearate, povidone, and colloidal silicon dioxide. The film-
`coating contains ferric oxides red and yellow, soy lecithin, polyethylene glycol 3350, polyvinyl
`alcohol, talc, and titanium dioxide.
`
`Regorafenib is indicated for the treatment of metastatic colorectal cancer who have been treated
`with,
` fluoropyrimidine-based chemotherapy. The
`recommended daily dose is 160 mg (4 tablets, 40 mg/tablet), to be taken once orally for three
`weeks followed by a one-week break.
`
`All CMC review deficiencies have been resolved for this application, and all related reviews are
`complete. An overall acceptable recommendation from the Office of Compliance was issued for
`this application on 05-SEP-2012. All container/carton and PI labeling comments have been
`issued to the Applicant, and the receipt of final labeling is pending.
`
`All CMC review issues have been resolved, and ONDQA recommends approval of this NDA
`pending the receipt of final acceptable labeling (PI and container/carton). There is
`confirmatory language for the action letter, located at the end of this review, regarding the
`granted expiration dating period.
`
`Administrative
`The original submission of this 505(b)(1) NDA was received on 27-APR-2012. Several solicited
`CMC amendments were also reviewed during the review cycle. The comprehensive CMC
`assessment is captured in the following reviews, respectively: Chemistry Review #1 (for the Drug
`Substance, 29-AUG-2012 by Dr. D. Lu), Chemistry Review #1 (for the Drug Product, 27-AUG-
`2012 by Ms. J. Jee) and the Biopharmaceutics Review (28-AUG-2012, Dr. E. Chikale).
`
`The NDA is supported by IND 75,642 and four (4) drug master files (DMFs). All DMFs were
`assessed for adequacy in the respective chemistry reviews.
`
`Drug Substance (regorafenib)
`Chemical Name: 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-
`fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate
`
`
`
`
`
`
`Molecular Formula C21H15ClF4N4O3 (H20)
`Molecular Weight 500.83 g/mol
`
`
`Reference ID: 3185235
`
`(b) (4)
`
`(b) (4)
`
`

`

`m4)
`Regorafenib is a new molecular entity and is manufactured as its monohydrate.
`Accordingly. regorafenib (water
`free) is the active drug substance present in regorafenib coated tablets. Regorafenib monohydrate
`is a
`M“) is practically insoluble in
`aqueous solutions.
`
`mm for the drug substance. This strategy was not
`The Applicant employs a
`altered during development. The Applicant identified and proposed Critical Process Parameters
`as part of the CMC dossier. The Application also provided adequate details in the Process
`Description. During the review, the Applicant was asked to provide a specification for an
`m", to provide additional justification for
`the proposed color specification. and to supply supporting information for methods validation.
`The Applicant’s collective responses satisfactorily resolved these deficiencies during the CMC
`revrew.
`
`The drug substance is relatively stable; no extraordinary storage precautions are required. The
`proposed re—test period of
`“M" when stored in the recommended container closure system
`and under the proposed storage conditions (25°C/60%RH) is granted.
`
`Drug Product — STIVARGA, 40 mg
`t pink, oval-shaped film-coated tablets.
`STIVARGA (regorafenib) Tablets are formulated as 1i
`and the following inactive ingredients:
`Each tablet contains 40 mg of regorafenib
`0"
`microcrystalline cellulose. croscarrnellose sodium, magnesium stearate. povidone, and colloidal
`silicon dioxide. The film-coating contains ferric oxides red and yellow, soy lecithin. polyethylene
`glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. The drug product will be marketed in
`packages containing 84 tablets. Each package contains three bottles, and each bottle contains 28
`tablets.
`
`mu) . One of the most
`The manufacturing process consists of
`significant identified review issues centered around the Applicant’s ability to sufficiently
`distinguish the presence of
`“M"
`during manufacture. This issue was specifically discussed in a 15-AUG-2012 teleconference
`with the Applicant. While the technical issue was effectively resolved through this interaction.
`the Applicant stated an intent to submit further validation information for an
`“m"
`. The Agency confirmed that this submission could be made in the post-
`approval arena. via current regulations and guidance.
`
`The Applicant also provided updated stability data on 24-AUG-2012, which was reviewed in this
`cycle. As captured in the Chemistry Review, these deficiencies/issues were resolved during the
`review clock. Related review information can be located in Chemistry Review #1 for the Drug
`Product, as well as the ONDQA Biopharmaceutics Review.
`
`While all container/carton and PI labeling comments have been issued to the Applicant,
`acceptable final labeling has not yet been received.
`
`Thefollowing language needs to be placed in the approval letter:
`
`Reference ID: 31 85235
`
`

`

`Reference ID: 3185235
`Reference ID: 3185235
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`09/06/2012
`
`Reference ID: 3185235
`
`

`

`
`
`STIVARGA® (Regorafenib)
`Tablets
`
`40 mg
`
`Bayer HealthCare Pharmaceuticals Inc.
`
`Drug Substance Section
`
`Division of Oncology Drug Products
`
`Donghao (Robert) Lu, Ph.D.
`Division I of Pre—Marketing Assessment
`Office of New Drug Quality Assessment
`
`Reference ID: 31 82424
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................6
`
`1. Recommendations ...................................................................................................................... 6
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 6
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 6
`
`II. Summary of Chemistry Assessments.........................................................................................6
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 6
`
`B. Description of How the Drug Product is Intended to be Used.......................................................... 7
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 7
`
`III. Administrative........................................................................................................................... 7
`
`A. Reviewer’s Signature ........................................................................................................................ 7
`
`B. Endorsement Block........................................................................................................................... 7
`
`C. CC Block .......................................................................................................................................... 7
`
`Chemistry Assessment .............................................................................................8
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data .........8
`
`S. DRUG SUBSTANCE ...................................................................................................................... 8
`
`A. APPENDICES ............................................................................................................................... 48
`
`R. REGIONAL INFORMATION ...................................................................................................... 48
`
`II. List Of Deficiencies And Responses .......................................................................................48
`
`Reference ID: 31 82424
`
`2
`
`

`

`
`
`Chemisz Assessment Section
`
`Chemistry Review Data Sheet
`
`1. NDA 203—085
`
`2. REVIEW NUMBER: 1
`
`3. REVIEW DATE: 29 AUGUST 2012
`
`4. REVIEWER: Donghao (Robert) Lu, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`PREVIOUS DOCUMENTS
`
`DOCUMENT DATE
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`SUBMISSION REVIEWED
`
`DOCUMENT DATE
`
`NDA 203—085
`
`NDA 203-085 (Amendment 007)
`
`NDA 203—085 (Amendment 0011)
`
`NDA 203—085 (Amendment 0012)
`
`NDA 203-085 (Amendment 0013)
`
`27-APR—12
`
`3-JULY-12
`
`13—AUG-12
`
`24-AUG—12
`
`28—AUG—12
`
`7. NAME & ADDRESS OF APPLICANT:
`
`NAME:
`
`ADDRESS:
`
`REPRESENTATIVE:
`
`Bayer Healthcare Pharmaceuticals, Inc.
`
`340 Changebridge Rd.
`Pine Brook, NJ 07058
`
`Philip Johnson, Deputy Director,
`Global Regulatory Affairs
`
`TELEPHONE:
`
`973—487—2000
`
`Reference ID: 31 82424
`
`

`

`
`
`Chemisz Assessment Section
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`PROPRIETARY NAME
`
`STIVARGA (Regorafenib)
`
`NON—PROPRIETARY NAME (USAN)
`
`Regorafenib
`
`CODE NAME] NUMBER (0NDC ONLY)
`
`BAY 73-4506
`
`CHENIISTRY TYPE I SUBNIISSION PRIORITY
`
`ll’
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`505(b)1
`
`10. PHARMACOL. CATEGORY:
`
`Multi kinase inhibitor
`
`11. DOSAGE FORM:
`
`12. STRENGTH/POTENCY:
`
`Tablet
`
`40 mg
`
`13. ROUTE OF ADMINISTRATION:
`
`Oral
`
`14. Rx/OTC DISPENSED:
`
`_—_—
`x Rx
`
`OTC
`
`15. SPOTS gSPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`SPOTS product — Form Completed
`
`x Not a SPOTS product
`
`l6. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Name (IU'PAC):
`
`Name (INN, USAN): Regorafenib
`Name (CAS):
`2-Py1idinecarboxamide, 4-[4-[[[[4-chloro-3-
`(trifluoromethyl)phenyl]amino]carbonyl]amino]-
`3-fluorophenoxy]-N-methyl-, hydrate (1:1)
`4-[4-({[4-chloro-3-(t1ifluoromethyl)phenyl]
`carbamoyl}amino)-3-fluorophenoxy]-N-methylpy1idine-
`2-carboxamide monohydrate
`(CAS) Registry Num: 1019206-88-2
`MOI. Formula:
`C21H15CIF4N403 ° H20
`Mol. Wt.:
`500.83
`
`Structural Formula:
`
`F
`
`I;
`
`Cl
`
`0
`
`0
`”A”
`
`o\©/‘Ln,cn3
`/ N
`
`x H20
`
`F
`
`Reference ID: 31 82424
`
`

`

`
`
`Chemistry Assessment Section
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`TYP
`
`E
`
`HOLDER
`
`ITEM
`REFERENCED
`
`COD
`E1
`
`STATUS
`
`2
`
`REVIEW
`COMPLET
`
`ED
`
`DATE
`
`1 Action codes for DMF Table:
`l — 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 "Connnents")
`
`2Adequate. Inadequate. or N/A: There is enough data in the application. therefore the
`DMF did not need to be reviewed.
`
`B. Other Documents:
`
`DOCUMENT
`
`DESCRIPTION
`
`APPLICATION NUMBER
`
`18. STATUS:
`
`CONSULTS &
`CMC RELATED
`REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`m Acceptable 03$)
`OSE DMEPA
`Acceptable (DP)
`
`2-MAY-12
`27-JUN 12
`-
`
`0C / CDER / FDA
`Jung Lee. RPh
`
`N/A
`
`EA
`
`Biopharm
`
`Pharm/Tox
`
`Micro Consultation
`
`See DP
`
`See DP
`
`Acceptable (DS)
`
`Anwar M. Goheer. PhD
`
`Reference ID: 31 82424
`
`

`

`
`
`Chemistry Assessment Section
`
`The Chemistry Review for NDA 203-085
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The review includes the evaluation of the CMC information provided in the original
`NDA and amendments received through 8/28/2012. The regorafenib monohydrate
`drug substance is recommended as APPROVAL from a CMC perspective,
`
`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 Substance and Drug Product
`
`1. Drug Substance
`
`The drug substance is regorafenib monohydrate. The chemical name is 4-[4-({[4-
`chloro—3-(trifluoromethyl)phenyl] carbamoyl}amino)—3-fluorophenoxy]—N—
`methylpyridine—Z—carboxamide monohydrate. It has a molecular formula of
`C21H15C1F4N403 - H20 and its molecular weight is 500.83.
`
`Data from the studies of elemental analysis, UV, IR, Raman, NMR and MS
`demonstrated that the structure was adequately defined. The
`are adequate for the manufacturing of the regorafenib monohydrate
`drug substance. As this is a new molecular entity, a methods validation request was
`sent for the HPLC method for the determination of assay and organic impurities.
`
`M (4)
`
`“(4) development of the drug substance
`The impurities detected during the
`were evaluated. Analytical methods were developed for the control of the impurities
`listed in the submission. Comprehensive information for all the impurities
`(mm
`were
`
`adequately presented.
`
`Regorafenib monohydrate drug substance was placed under the ICH recommended
`conditions for stability test. The drug substance was physically and chemically stable
`based on evaluation of the testing data. A retest period of
`mm was acceptable
`for the drug substance.
`
`Reference ID: 31 82424
`
`

`

`
`
`Chemisz Assessment Section
`
`2. Drug Product
`
`See drug product review document.
`
`B. Description of How the Drug Product is Intended to be Used
`
`See drug product review document.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`Bayer has submitted adequate CMC information to support the drug substance section
`in this NDA. All the remaining issues have been adequately addressed by the
`applicant (see the end of this document).
`
`1]]. Administrative
`
`A. Reviewer’s Signature
`
`\s\
`
`Donghao (Robert) Lu, Chemistry Reviewer
`
`B.
`
`Endorsement Block
`
`\s\
`
`Nallaperum Chidambaram, Branch Chief (Acting)
`
`C. CC Block
`
`45 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 31 82424
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`08/30/2012
`
`NALLAPERUM CHIDAMBARAM
`08/30/2012
`I concur.
`
`Reference ID: 3182424
`
`

`

`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 203,085
`
`
`Stivarga™ (regorafenib) Tablets (BAY 73-4506)
`
`
`
`Bayer Healthcare Pharmaceuticals, Inc.
`
`
`
`
`Josephine Jee
`
`Office of New Drug Quality Assessment
`Division of New Drug Quality Assessment I
`Branch II
`
`For
` Division of Drug Oncology Products 2
`Office of Hematology and Oncology Products
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3184664
`
`
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet...................