CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -729
`
`CHEMISTRY REVIEW! S!
`
`

`

` CHEMISTRY REVIEW
`
`NDA 21-729
`
`Abilify® DiscmeltTM (aripiprazole) Orally Disintegrating
`v
`Tablets
`
`Otsuka PharmaceuticalCo. Ltd
`
`Gurpreet Gill—Sangha, Ph.D.
`OFFICE OF NEW DRUG AND QUALITY ASSESSMENT
`(ONDQA)
`Review of Chemistry, Manufacturing, and Controls
`
`

`

`CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents
`
`......
`
`....... . .......
`
`......
`
`........... . .............2
`
`Chemistry ReView Data Sheet"...ooooooooo O......ocgoloolonaéooooooooon.iiiiiii0.0.... ..... on.0000000000-0-04
`
`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 ........................................................ 1 l
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 1 1
`
`III. Administrative ......................................................................................................................... 11
`
`A. Reviewer’s Signature ............................................................
`
`................................. 11
`
`B. Endorsement Block ......................................................................................................................... 11
`
`C. CC Block ........................................................................................................................................ 11
`
`Chemistry Assessment ..................................... ...................................................... 12
`
`LABELING ........................................................................................41
`
`Attachment 1: BER ................................................................................................................-.......47
`
`Attachment 2: EIR Dated 5/26/2004 ............................................................................................ :51
`
`Attachment 3: EIR from 11-9 to 12-6—2004 Inspection ............................................................... 52
`
`Attachment 4: EIR from 11-9 to 12-6-2004 Inspection ............................................................... 55
`
`Attachment 5: Certificate of Analysis for Commercial 10- and 15-mg batches...........................58
`
`

`

`CHEMISTRY REVIEW
`
`List of Tables:
`‘
`Table 1: Final Updated Abilify® DiscmeltTM ODT Specifications
`Table 2: Aripiprazole ODT Excipient Blends Placed on Stress Stability _—————
`
`12
`
`14
`
`Table 3: Potency of Aripiprazole and Aspartame on Stress Stability and % of Degradants Famed
`Table .4: Tablet Content Uniformity Results from PJ Batches of 10, 15, 20 and 30 mg Abilify ODT
`Table 5: Tablet Potency Results for PJ Batches 10, 15, 20 and 30 mg Abilify ODT
`_
`Table 6: —— ‘ Compression Process Yield Specifics for PJ Batches
`Table 7: Tablet Compression Trend Data for Aripiprazole ODT
`Table 8: Compression Process Yield Specifics for Long term Stability Batches of Aripiprazole ODT Using
`— Tablet Press
`
`15
`. 20
`20
`21
`22
`
`23
`
`Table 9: Compression Process Yield Specifics for Process Justification (PJ) Batches of Aripiprazole ODT
`24
`Using — Tablet Press
`_
`Table 10: Compression Rejection and Yield Specifics for Validation Batches of 10- and lS-mg Aripiprazole
`ODT Using — Tablet Press
`25
`Table 11: Compression Process Yield Specifics for Post-Validation Commercial Batches of lS-mg
`Aripiprazole ODT using ‘ _ Tablet Press
`Table 12: Tablet Compression Trend Data fro Aripiprazole ODT Updated
`Table [3: Compression Process Yield Specifics for Commercial Batches of 10-mg Aripiprazole ODT using
`28
`the — 1 Tablet Press
`29
`Table 14: Test Results for Batch #2H56081 for 10-mg Aripiprazole ODT
`Table 15: Sampling Plan for Tablet Compression of Aripiprazole ODT Manufactured at Mayaguez, Puerto
`Rico
`30
`Table 16: Sampling Plan for Tablet Compression Using — Tablet Press
`31
`_ Table 17: Length of Time Taken for Tablet Compression of PJ Batches
`31
`Table 18: Disintegration Data for Aripiprazole ODT Process Justification Batches Using USP Disintegration
`test <701> ,
`33
`Table 19: Disintegration Data for Aripiprazole ODT LTSS Samples Stored _ Using the USP
`<701>
`Table 20: Disintegration Data for Aripiprazole ODT Using USP401> Disintegration Test
`I Table 21: Shipping Study on Abilify ODT from Manufacturing Facility to Packaging Site
`Table 22: Summary of Analytical Tests for Pre— and Post—Shipping Study
`Table 23: Comparison Data for Compression Events from Validation and Commercial Batches of
`Aripiprazole ODT
`
`33
`34
`35
`36
`
`41
`
`26
`27
`
`I
`
`

`

`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 21-729
`
`2. REVIEW #2 3
`
`3. REVIEW DATE: June 7, 2006
`
`4. REVIEWER: Gurpreet Gill-Sangha, Ph.D.
`
`5. PREVIOUS DOCUMENTS: None
`
`Previous Documents
`
`Original NDA submission
`Amendment C
`Amendment BC '
`Amendment BC
`Amendment BC
`Amendment BC
`Chemistry review #1
`Chemistry review #2
`Approvable (AE) Letter
`
`6. SUBMISSION(S) BEING REVIEWED:
`Submission; 3) Reviewed
`Amendment C
`Amendment AZ
`Amendment BZ
`Amendment BL
`Amendment (by email)
`Amendment (by email)
`Amendment (by email)
`
`_
`
`Document Date
`
`December 22. 2003
`January 13, 2004
`March 31, 2004
`July .8, 2004
`August 4, 2004
`August 20, 2004
`October 15, 2004
`October 29, 2004
`October 22, 2004
`
`Document Date
`October 28, 2004
`December 12, 2005
`April 13, 2006
`May 12, 2006
`May 15, 2006
`June 1, 2006
`June 6, 2006
`
`7.’ NAME & ADDRESS OF APPLICANT:
`
`Otsuka Pharmaceutical Co., Ltd.
`2—9 Kanda Tsukasa-cho
`
`Representative*: Telephone:
`
`
`
`Chi oda-ku Tok 0, 101-8535, Jaan
`Kusuma Mallikaarjun, Ph.D., Senior Director,
`'
`Regu_latory Affairs/Abilif
`
`(301) 990-0030
`
`Page 4 of 62
`
`

`

` CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`* It is noted that the following is the authorized US agent name and address:
`
`Kusuma Mallikaarjun, Ph.D., Senior Director
`Otsuka Maryland Research Institute, Inc.
`2440 Research Boulevard
`
`Rockville, MD 20850
`
`* Cover letter states that Bristol—Myers Squibb (EMS) is delegated to act on behalf of Otsuka
`Pharmaceuticals Co. (OPC) for correspondence. The CMC contact is:
`
`Mary Peters, Director, Global Regulatory Sciences — CMC @ (609) 818—5 521
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Abilify
`b) Non-Proprietary Name (USAN): Aripiprazole
`0) Code Name/# (ONDC only): None
`d) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b) (1)
`
`10. PHARMACOL. CATEGORY: Schizophrenia
`
`1 l. DOSAGE FORM:
`
`Orally Disintegrating Tablets
`
`12. STRENGTH/POTENCY:
`
`10, 15, 20, and 30 mg *'(* will initially launch 10 and 15
`mgA
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED:
`
`_X_Rx
`
`OTC
`
`
`15. SPOTS gSPEClAL PRODUCTS ON-LlNE TRACKING SYSTEM);
`SPOTS product — Form Completed
`
`
`X
`
`Not a SPOTS product
`
`l6. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`CA Name:
`
`USAN Name:
`Chemical Formula:
`
`7—[4-[4-(2,3-Dichlorophenyl)- l -piperazinyl] butoxy]—3,4—
`dihydrocarbostyril
`Aripiprazole
`C23H27C12N302
`
`Molecular Weight:
`
`448.39
`
`Page 5 of 62
`
`

`

`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`CAS registry #:
`Laboratory Code:
`Structure:
`
`_
`1279722—12-9
`OPC-l4597, OPC-3l, BMS-337039-01
`
`Cl
`
`-Cl m
`
`N—CHZCIlgCHzCHzO
`N
`\__/
`
`0
`
`N
`H
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs: None for this review
`
`
`
`
`
`CODE‘
`
`STATUS2
`
`DATE
`REVIEW
`CONmLETED
`
`COMMENTS
`
`BIL/[F
`
`TYPE
`
`HOLDER
`
`
`
`REFéEI‘gCED
`
`
`' 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 "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: None for this review
`
`DOCUMENT
`
`18.STATUS:
`
`
`
`
`APPLICATION NUMBER
`
`I
`
`DESCRIPTION
`
`‘
`
`
`
`ONDQA:
`
`CONSULTS/
`
`REVIEWER
`DATE
`CMC RELATED RECOMMENDATION
`
`
` Biometrics
`
`
`Shirnette Ferguson
`24, 2006
`Janua
`Acceotable
`
`
`Acceptable
`Refer to CMC review #1
`Sonia Tabacova, Ph.D.
`Pharm/Tox
`'
`
`Biopharm
`Acceptable
`January 22, 2006,
`Kofi Kumi, PhD.
`
`review #2
`
`
`Page 6 of 62
`
`

`

` CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`Methods Validation Acceptable
`
`As per CMC review #1
`
`
`
`Acceptable — categorical As per CMC review #1
`exclusion _ranted
`Nota. licable
`
`Gurpreet Gill-Sangha,
`PhD.
`
`Denise Toyer, PharmD.
`
`Gurpreet Gill-Sangha,
`Ph.D.
`
`OPDRA (DMETS)
`
`Acceptable
`
`May 31, 2006, review
`#2
`
`' E
`
`A
`
`Page 7 of 62
`
`

`

` CHEM-[STRY REVIEW
`
`Executive Summary Section
`
`The Chemistry Review for NDA 21-729 ,
`
`The Executive Summary
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`NDA 21-729 for Abilify® DiscmeltTM (aripiprazole) Orally Disintegrating Tablets is
`recommended for APPROVAL from the CMC standpoint. Bristol Myers Squibb has
`addressed all the CMC issues as outlined in Chemistry Review’s #1, #2 and #3 and in
`addition, FDA’s Office of Compliance has issued an overall acceptable
`recommendation for all manufacturing and testing sites on January 24, 2006. A
`separate audit by'FDA Compliance conducted on May 24 and 25, 2006 also found
`specific concems with BMS site in Mayaguez acceptable (see Attachment 4).
`
`. Recommendation on Phase~4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`None as per this review.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Abilify (aripiprazole) Orally disintegrating tablets (ODT) are indicated for the
`treatment of schizophrenia. Abilify ODT is a new aripiprazole dosage form especially
`for thosepatients who may have difficulty swallowing tablets. Currently, Abilify
`tablets in strengths of 2, 5, 10, 15, 20 and 30 mg approved (November 15, 2002) under
`NDA 21-436 are available. Abilify ODTs are to be marketed as 10, 15, 20, and 30 mg
`‘orally disintegrating tablets in unit blisters of 30 and 100 counts per pack. ‘—
`
`Wm
`
`BMS states that
`
`_
`
`initially they 9'ropose to launch only the 10 and 15 mg strengths.
`
`The drug substance aripiprazole is same as the one approved in NDA 21-436. It is
`noted that the original NDA 21-436 was not in the CTD-Q format as the current NDA
`and certain sections of drug substance are different in the CTD-Q format and therefore
`could not be reviewed as CTD—Q application. However, since the drug has been
`approved and marketed, the relevance of these sections is less of a concern.
`Aripiprazole is manufactured by Otsuka Pharmaceuticals, Japan and its specifications
`are the same as in the approved NDA 21-436. Certificate of analysis (CoAs) of five
`aripiprazole batches used to manufacture the Abilify ODT batches were provided. -
`-———"
`date was granted to aripiprazole at 25 °C/60%RH as part of NDA 21-436.
`
`Page 8 of 62
`
`

`

` CHEMISTRY REVIEW
`
`Executive Summary Section
`
`Abilify ODT is formulated for oral administration in strengths of 10, 15, 20 and 30 mg.
`The tablets contain the active aripiprazole, calcium silicate ‘ '
`
`— croscarmellose. sodium and crospovidone
`" '
`silicon'dioxide
`_— microcrystalline cellulose —— magnesium stearate
`—— xylitol, aspartame and acesulfame potassium _ In addition,
`creme de vanilla is used as a flavor and tartaric acid ~—_ Red
`ferric oxide (pink) is used for 10 and 30 mg tablets and yellow ferric oxide (yellow) is
`used for 15 mg tablets. 20 mg tablets are white in color (no colorant added). Even
`though the 10 and 30 mg are identical in color (pink), they are distinguishable in size
`and debossings for individual strengths.
`
`The ODTs are manufactured —-———-— followed by .—
`form the tablets.
`In this resubmission, BMS has provided a well designed study to
`establish that aspartame does not interact with aripiprazole or other excipients in the
`CDT formulation.
`In addition, BMS has provided rationale andjustification for use of
`croscarmellose sodium —-—'— in addition to crospovidone for the CDT
`formulation by demonstrating the dissolution profiles of the Abilify ODT containing
`croscarmellose sodium are similar to the Abilify tablets.
`
`The commercial batch size is -——'—— tablets varying by the
`strength) and — batches were manufactured for this NDA as — batches of '—
`30 mg,
`'- batches of 10 and 15 and - batch of 20 mg. All the batches were
`manufactured at Bristol Myers Squibb (BMS), Mayaguez, Puerto Rico. A -
`tablet press v was used for batches manufactured for this NDA and
`based on the information from FDA inspection during May 2004, batches were rejected
`due toE tablet prOblems. BMS proposed to change
`————— Lablet press _— . BMS has provided data
`for 10, 15, 20 and 30 mg Abilify ODT tablets for Process Justification — .
`validation — ;and commercial ‘ — .of 10'— and 15- mg batches).
`It is noted
`that the rejection rate from Process Justification (PJ) and validation batches was still
`high at approximately up to —— . Data requested during several
`teleconferences between BMS and Drs. Gurpreet Gill—Sangha and Thomas Oliver and
`the FDA audit conducted during May 24-25, 2006 revealed that the c— tablet press
`was operated —I_— for the Process Justification and validation batches due to
`software problems. However, the software has been validated for the commercial
`batches and the — is now under —— , resulting in small amounts
`of rejected materials —-—.—‘ ' The sampling plan for the — tablet
`press is detailed in this review and it is acceptable to FDAs Office of Compliance also.
`
`No specification for disintegration time was propoSed in the original submission. BMS
`responded in mid-August 2004 to FDA’s request in April 2004 for a disintegration
`specification. The responses were submitted on August 20, 2004 for all CMC issues
`(including those communicated in the 74-day letter).
`It is noted that BMS did not
`request a pre-NDA meeting with the chemistry team.
`Initially BMS proposed a
`
`Page 9 of 62
`
`

`

`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`disintegration time of NMT — which was unacceptable and FDA requested
`BMS to propose a disintegration specification based on the recommendation of the
`In
`Advisory Committee for Pharmaceutical Science meeting in October 21-22, 2003.
`this resubmission, BMS has proposed a disintegration time of NMT 60 seconds which
`is acceptable as per the Advisory Committee recommendation. BMS has provided data
`from _ batches which shows the disintegration time to be ——
`In addition, as per FDAs request BMS has updated the disintegration method to the
`USP disintegration method <701>. The specifications of identity by f ——
`— were stated as “confirmed” which was unacceptable in the original submission.
`BMS has updated the identity test to include the —— . tests for routine
`testing.
`In addition, the dissolution specification of Q NL'I‘ — in 30 minutes was
`recommended as per review by Dr. Kofi Kumi during the Original submission.
`
`In the original submission, all the batches of Abilify ODT manufactured at BMS,
`Mayaguez, Puerto Rico were also packaged-at the same site. However, the primary
`commercial packager for Abilify ODT is BMS, Mt. Vernon, Indiana and the secondary
`contract packagers are .————-————-—_
`—— The entire stability data collected including -— at 25 °C/60%RH,
`—; at 40 °C/75%RH and 50 °C were from batches packaged at the BMS,
`Mayaguez, Puerto Rico site. No data were provided to show that the Abilify ODTs
`were acceptable prior to packaging at the commercial packaging sites and were able to
`withstand the transportation and bulk storage conditions. Due to nature of ODTs,
`possible softening and increased friability could occur. Therefore, BMS was requested
`to demonstrate that commercial Abilify ODTs (manufactured by BMS in Mayaguez,
`Puerto Rico, packaged in bulk containers, transported to a packaging site, and packaged
`in blisters) will remain within specifications at release and stability. BMS has provided
`a simulated shipping study in this resubmission to compare the pre- and post— shipping
`data which shows that results for moisture, hardness, and friability are similar. The
`disintegration time was below -— with the BMS method instead of the proposed
`USP<701> for the commercial batches. Based on the stability data provided and the
`simulated study, an expiry of 24 months at 25 °C/60%RH is acceptable for Abilify
`ODT.
`
`BMS has clarified in this resubmission that the specifications and test limits for post—
`approval stability are the same as stability and release except for not monitoring water,
`hardness and friability on post-approval. It should be noted that the commercial Abilify
`ODT will be blister packaged which do not experience the level of abrasion as the
`bottled tablets. An unknown impurity~ was
`observed under accelerated conditions in the original submission. FDA had requested
`that this impurity should be identified and characterized as it is seen —-
`~ . BMS has provided acceptable rationale that the
`
`W
`
`Page 10 of 62
`
`

`

`’ CHEMISTRY REEVIEW
`i
`
`Executive Summary Section
`
`Information is provided for the labels of bulk containers, unit dose blisters and their
`cartons. The package insert also contains the precautionary statement for aspartame in
`the “Precautions” section as per 21 CFR 201.21(c) for amount ofphenylalanine.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Aripiprazole orally disintegrating tablets will be supplied in four strengths: 10, 15, 20
`and 30 mg. The orally disintegrating tablets will be: packaged and marketed in unit
`dose aluminum/aluminum blisters. The trade packages for market launch will contain '
`30 and 100 tablets.
`
`The recommended starting and target dose for Abilify ODT is 10 or 15 mg/day
`administered as a once-a-day schedule without regard to meals or liquid. The blister
`should not be opened until ready to administer. The" tablet disintegration occurs in
`saliva.
`
`An expiry of 24 months at 25 °C/60%RH is acceptable for Abilify ODT.
`
`. Basis for Approvability or Not-Approval Recommendation
`
`NDA 21-729 for Abilify® DiscmeltTM Orally Disintegrating Tablets is recommended
`for APPROVAL based on the following:
`o Adequate responses to CMC concerns related to. the drug product sections as listed
`in Chemistry review #1 dated October 15, 2004 and included in the October 22,
`2004 Approvable letter.
`.
`o Acceptable recommendation from FDA Compliance regarding cGMP status of
`manufacturing, packaging, controls and testing facilities dated January 24, 2006 and
`the Memo for FDA audit conducted .on May 24 — 25, 2006.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`See electronic signature in Division File System (DFS).
`
`B. Endorsement Block
`
`See electronic signatures in DFS
`
`C. CC Block
`
`See DFS
`
`Page 11 of 62
`
`

`

`' 5i
`
`Page(s)Withheld .
`
`_-_'/_ ’ Trade Secret / Confidential
`
`Draft Labeling
`
`Deliberative Process ‘
`
`Withheld Track Number: Chemistry— 2
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation ofthe electronic signature.
`
`Gurpreet Gill-Sangha
`6/7/2006 07:33:07 AM
`CHEMIST
`
`CMC review #3 for NDA 21-729
`
`Thomas Oliver
`
`6/7/2006 07:59:08 AM
`CHEMIST
`
`

`

`Initial Quality Assessment
`1
`Branch I
`
`0ND Division: Division of Psychiatry Products
`NDA:
`21-729
`
`Applicant: Otsuka Pharmaceutical Co. Ltd
`Letter Date:
`lZ—DEC—OS
`
`13—DEC-05
`Stamp Date:
`13_—JUN-06
`PDUFA Date:
`AbilifyTM Orally Disintegrating Tablets
`Trademark:
`aripiprazole
`Established Name:
`Dosage Form: Orally Disintegrating Tablets to 10, 15, 20 and 30 mg)
`Route of Administration: Oral
`'
`
`Indication:
`Assessed by:
`
`Schizophrenia
`Thomas F. Oliver, Ph.D.
`
`Summary
`Abilify® (aripiprazole) Orally Disintegrating Tablets were developed to treat
`schizophrenia, especially for those patients who have difficulty swallowing tablets.
`Aripiprazole was discovered by Otsuka Pharmaceutical co., Ltd. and co—developed with
`Bristol-Myers Squibb Company. The sponsor has two other approved aripiprazole
`products: 1) Abilify Tablets [AP, 15—NOV-02], and 2) Abilify Oral Solution [AP, 10—
`DEC-‘04]. The original NDA was submitted December 22, 2003. The sponsor was sent
`an AB letter dated October 22, 2004. The sponsor has responded to that letter in an
`electronic submission dated December 12, 2005.
`
`Comments and Recommendation:
`
`The sponsor has responded to each of the issues detailed in the October 22, 2004 AE
`letter. The sites have been resubmitted to the Office of Compliance and have been found
`acceptable as of January 24, 2006. As Dr. Gurpreet Gill-Sangha evaluated the original
`NDA, she would be a prudent choice as the CMC reviewer of this resubmission.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Thomas Oliver
`
`2/1/2006 10:01:30 AM
`CHEMIST
`'
`
`'Ramesh Sood
`
`2/2/2006 09:53:10 AM
`CHEMIST
`
`

`

` CHEMISTRY REVIEW
`
`NDA 21-729
`
`AbilifyTM (aripiprazole) Orally Disintegrating Tablets
`
`Otsuka Pharmaceutical Co. Ltd ‘
`
`Gurpreet Gill-Sangha, Ph.D.
`DIVISION OF. NEUROPHARMACOLOGICAL DRUG
`
`Review of Chemistry, Manufacturing, and Controls
`
`PRODUCTS
`
`'
`
`

`

` CHEMISTRY REVIEW .
`
`Table of Centents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review DataSheet ........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 .......................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 9
`
`III. Administrative ....................................................................... '. ................................................... 9
`
`A. Reviewer’s Signature .....V................................................................................................................... 9
`
`B. Endorsement Block ........................................................................................................................... 9
`
`C. CC Block ....................................................................................................................‘...................... 9
`
`Chemistry Assessment ....................................................-....................................... 10
`
`ESTABLISHMENT INSPECTION .............................................................................................. 10
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`

`

`
`
`. CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 21—729 _
`
`2. REVIEW #: 2.
`
`3. REVIEW DATE: October 28, 2004
`
`4. REVIEWER: Gurpreet Gill—Sangha, Ph.D.
`
`5. PREVIOUS DOCUMENTS: None
`
`Previous Documents
`
`Original NDA submission
`Amendment C
`
`Amendment BC
`Amendment BC
`Amendment BC
`Amendment BC
`
`6. SUBMISSION(S) BEING REVIEWED:
`Submission 5 Reviewed
`
`Original NDA submission
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`December 22. 2003
`
`January 13, 2004
`March 3] , 2004
`
`July 8, 2004
`August 4, 2004
`August 20, 2004
`
`Document Date
`December 22. 2003
`
`Otsuka Pharmaceutical Co., Ltd.
`
`2—9 Kanda Tsukasa—cho
`
` (203) 677—3810
`
`Re resentative'
`p
`'
`
`Telephone:
`
`Chiyoda—ku Tok 0, 101—8535, Jaan
`Ms. Susan H. Behling, Director, Regulatory Science,
`Bristol—M ers Suibb Co.
`
`‘ 8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Abilify
`b) Non—Proprietary Name (USAN): Aripiprazole
`c) Code Name/# (ONDC only): None
`d) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b) (l)
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`Page 3 of 14
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`CHEMISTRY REVIEW
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`Chemistry Review Data Sheet
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`10. PHARMACOL. CATEGORY: Schizophrenia
`
`ll. DOSAGE FORM:
`
`Orally Disintegrating Tablets
`
`12. STRENGTH/POTENCY:
`
`-' 10, 15, 20, and 30 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED: _X_Rx
`
`OTC
`
`15.
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`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:
`
`CA Name: ‘
`
`USAN Name:
`Chemical Formula:
`
`Molecular Weight:
`CAS registry #:
`Laboratory Code:
`Structure:
`
`7—[4—[4—(2,3-Dichlor0phenyl)—1—piperazinyl]butoxy]—3,4—
`dihydrocarbostyril
`‘
`AIipiprazole
`C23H27C12N302
`
`448.39
`1279722712—9
`OPC-14597, OPC—31, BMS-337039-01
`
`N.
`
`N—CH2CH2CII2CH20
`
`N
`:11
`
`0
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs: None for this review
`
`
`COMMENTS ITEM
`
`TYPE
`
`HOLDER
`.
`
`REFERENCED
`
`CODE]
`
`STATUS2
`
`,
`
`DATE
`REVIEW ,
`COMPLETED
`
`I 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
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`. CHEMISTRY REVIEW
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`Chemistry Review Data Sheet
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`5 — Authority to reference not granted
`6 — DMF not available '
`'
`
`7 — Other (explain under "Comments")'
`
`2 Adequate, Inadequate, 0r N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents:
`
`
`
`
`DOCUMENT
`
`l
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`18. STATUS:
`
`0NDC :
`
`
`
`
`
`
`REVIEWER
`
`
`CONSULTS/ CMC
`RELATED
`REVIEWS
`
`
`
`
`
`Pharm/Tox
`
` RECOMMENDATION
`
`
`Kofi Kumi, PhD.
`
`
`
`
`
`
` Gurpreet Gill—San
`
`
`Acceptable
`August 13, 2004
`Kristina C. Amwine,
`
`
`
`
`
`PharmD.
`
`
`
`
`
`
`Acceptable — categorical As per this review
`exclusion _ranted
`
`Not a licable ——
`
`
`NotA licable
`
`Withheld
`
`
`
`
`
`dated October 13, 2004
`
`USAN Available
`
`-
`
`
`
`Gurpreet Gill-Sangha, Ph.D.
`
`Methods Validation
`
`OPDRA (DMETS)
`
`
`
`
`
`
`-
`
`
`
`
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`CHEMISTRY REVIEW
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`Executive Summary Section _
`
`The Chemistry Review for NDA 21-729
`
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`NDA 21-729 for AbilifyTM (aripiprazole) Orally Disintegrating Tablets is
`recommended NOT APPROVABLE from the CMC standpoint. The FDA’s Office of
`Compliance has issued a Withhold recommendation due to unresolved cGMP issues for
`the only drug product manufacturing site (CFN # 2627673) in Mayaguez, Puerto Rico.
`The approval is contingent on an overall acceptable recommendation from FDA
`Compliance and adequate responses to CMC deficiencies outlined in Chemistry review
`#1 dated October .15, 2004.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`None as per this review.
`
`11. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)l
`
`Abilify (aripiprazole) Orally disintegrating tablets (ODT) are indicated for the
`treatment of schizophrenia. Abilify ODT is a new aripiprazole dosage form especially
`for those patients who may have difficulty swallowing tablets. Currently, Abilify
`tablets in strengths of 2, 5, 10, 15, 20 and 30 mg approved (November 15, 2002) under
`NDA 21—436 are available. Abilify ODTs are to be marketed as v 10, 15, 20, and 30
`mg orally disintegrating tablets in unit blisters of 30 and 100 counts per pack.
`
`The drug substance aripiprazole is same as the one approved in NDA 21—436. It is
`noted that the original NDA 21—436 was not in the CTD—Q format as the current NDA
`andcertain sections of drug substance are different in the CTD—Q format. However,
`since the drug has been approved and marketed, the relevance of these sections is less
`of a concern. Aripiprazole is manufactured by Otsuka Pharmaceuticals, Japan and its
`specifications are the same as in the approved NDA 21-436. Certificate of analysis
`(CoAs) of five aripiprazole batches used to manufacture the Abilify ODT batches were
`provided. ~ date was granted to aripiprazole at 25 °C/60%RH as part of
`NDA 21—436.
`
`Abilify ODT is formulated for oral administration in strengths of o 10, 15, 20 and 30
`mg. The tablets contain the active aripiprazole, calcium silicate as
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`Page 6 of 14
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`CHEMISTRY REVIEW
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`Executive Summary Section
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`-———-— croscarmellose sodium and crospovidone as
`.— silicon dioxide as —_ t, microcrystalline
`cellulose — magnesium stearate as ‘ , xylitol, aspartame and acesulfame
`potassium as sweeteners. In addition, creme de vanilla is used as a flavor and tartaric
`acid is used as —— FD&C Blue #2 Aluminum Lake (blue) is used as color
`for 5 mg tablets, red ferric oxide (pink) is used for 10 and 30 mg tablets and yellow
`ferric oxide (yellow) is used for 15 mg tablets. 20 mg tablets are white in color (no
`colorant added). Even though the 10 and 30 mg are identical in color (pink), they are -
`distinguishable in size and debossings for individual strengths.
`
`The ODTs are manufactured _-————— followed by ——
`form the tablets. No data was provided to show compatibility of excipient aspartame
`with the active or other excipients. In addition, no justification is provided in the
`pharmaceutical development section for use of croscarmellose sodium .—
`—- in addition to crospovidone. The commercial batch size is ——
`—— tabletsvarying by the strength) and an batches were manufactured for
`this NDA as «II-batches of an 30 mg,
`:— batches of 10 and 15 and - batch of
`20 mg. All the batches were manufactured at Bristol Myers Squibb (BMS), Mayaguez,
`Puerto Rico. A -— tablet press was used for batches manufactured for this NDA
`and based on the information from FDA inspection, a significant number of batches
`were rejected due to —————————-
`tablet problems. The sponsor
`proposes to change from a —— tablet press post—approval for
`commercial batches without any validation to be provided to the Agency. Sponsor is
`requested to provide tablet data using the —— tablet press with one batch of each
`strength of Abilify ODT to show validation of the — tablet press.
`
`No specification for disintegration time was proposed in the original submission. BMS
`responded in mid-August 2004 to FDA’s request in April 2004 for a disintegration
`Specification. The responses were submitted on August 20, 2004 for all CMC issues
`(including those communicated in the 74—day letter). It is noted that BMS did not
`request a pre—NDA meeting with the chemistry team. BMS has provided data from
`— batches which shows the disintegration time to be .—
`‘ however, they have proposed a disintegration time of NMT —— which is
`unacceptably long for an ODT and also the batch data for — batches shows the
`disintegration time to be ¢—-——-
`FDA will request BMS to propose a
`disintegration specification based on the recommendation of the Advisory Committee
`for Pharmaceutical Science meeting in October 21-22, 2003. The Advisory committee
`stated that a disintegration time of even 60 seconds was too long for an orally
`disintegrating tablet. In addition, BMS will be requested to update the disintegration
`method to mimic the criteria similar to the USP disintegration method <701>. The
`specifications of identity by —-""_"
`are currently stated as “confirmed”
`which is unacceptable. BMS will be requested to provide more precise specifications
`for identity by —————— and also include —’ as for routine release
`testing. In addition, the dissolution specification of Q NLT .- . in 30 minutes is
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` CHEMISTRY REVIEW
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`Executive Summary Section
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`recommended as per review by Dr. Kofi Kumi. BMS is requested to provide the
`updated drug product specifications to reflect all the changes.
`
`All the #- batches of Abilify ODT manufactured at BMS, M