CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -729
`
`APPROVABLE LETTER
`
`

`

`b“ sum“
`
`
`
`S/é DEPARTMENTOFHEALTH&HUMAN SERVICES PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21—729
`
`Otsuka Pharmaceutical, Inc.
`
`Attention: Kusuma Mallikaarjun, PhD.
`2440 Research Boulevard
`
`Rockville, MD 20850
`
`Dear Dr. Mallikaarjun:
`
`Please refer to your new drug application (NDA) dated and received December 22, 2003, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Abilify (aripiprazole) Orally
`Disintegrating Tablets.
`-
`,
`
`We acknowledge receipt of your submissions of January 13, March 31, July 8, August 4, and August
`20, 2004.
`-
`
`We completed our review of this application, as submitted, with draft labeling, and it is approvable.
`Before the application may be approved, however, it will be necessary for you to address the following
`issues.
`
`1. Please provide compatibility data for aspartame with the active and other excipients in the drug
`product formulation, such as xylitol, to demonstrate that aspartame does not interact.
`
`2. You stated that croscarmellose sodium is to be used ‘——-—————
`
`crospovidone. However, no rationale is provided for use of croscannellose sodium as a —
`-————
`In addition, based on the Handbook of Pharmaceutical Excipients,
`croscarrnellose sodium can show incompatibilities and requires special storage conditions. Please
`provide data to show its compatibility with the active and other excipients.
`'
`
`3. You have proposed using the — tablet press for the manufacture of commercial batches,
`however, you have provided no batch data derived from this tablet press. Please provide batch data
`using the — tablet press for one batch of each strength of Abilify CDT.
`
`4. Please explain the testing results from the tablet compression of batch #2H56081 (10 mg) and
`batch #2G58279 (30 mg) where approximately _— respectively, of — batches
`were rejectedW Provide the sampling plans used for
`testing batches
`for
`tablet weight, potency,
`tablet hardness and disintegration during the
`compression process.
`
`5. The specification that you have provided for the identification of aripiprazole in the drug product is
`“confirmed” for both the IR and HPLC test methods. This is not an acceptable specification as it is
`
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`NDA 21—729
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`Page 2
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`vague and inconclusive. Please provide a more suitable specification for the identification of the
`drug product. You indicated that the — method for identification would not be part of the
`-"—-——— .
`Identification tests should be specific for a drug substance (e.g.,1 —,
`Identification solely by a single -—-——— is not regarded as~being specific.
`Provide an acceptable specification limit for the --
`method or a second identification test for
`aripipraZole in the drug product (e.g.,M
`
`M -
`
`———-— Refer» to ICH Guidance Q6A Specifications: Test Procedures and Acceptance
`Criteria for New Drug Substances and New Drug Products.
`
`Please
`is unacceptable.
`6. Your proposed disintegration time specification of NMT —.
`propose an' updated disintegration time limit
`in the drug product specifications (refer to the
`Advisory Committee for Pharmaceutical Science, October 21— 22, 2003).
`
`In addition, the disintegration method statesw
`
`the
`
`w —
`
`——_—— Please provide updated criteria for
`disintegration method and updated drug product release specifications.
`
`7. The following pertain to the stability of the Aripiprazole ODT:
`
`a. The stability data provided for Abilify ODT batches (manufactured and packaged at Mayaguez,
`Puerto Rico) constitutes supportive stability data. Due to the possible softening and
`increased friability of the CDT, you will need to demonstrate that these tablets can be shipped
`in bulk containers and packaged at
`the proposed commercial sites in ‘ ‘1
`— Provide information on bulk containers shipping conditions and release data for
`the bulk batch at the packaging sites Provide stability data from commercial packaging sites to
`demonstrate comparability with the stability data collected from Mayaguez Puerto Rico.
`
`b. You have identified an unknown impurity at — under accelerated conditions. Have you
`identified and characterized this unknown impurity at —
`
`c. Please provide specification limits for each test method in the long—tenn stability protocol as
`well as the post-approval stability prot0col.
`In addition, the post-approval stability protocol
`should monitor for water, hardness and friability.
`
`8. Refer to your labeling for the following comments:
`
`a. Please provide labels for bulk containers for'packaging and shipping and updated labels
`(containing trade name) for unit dose blisters and their cartons.
`
`b. The correct molecular weight for aripiprazole as per the USP Dictionary is 448.39. Please
`correct the molecular weight for aripiprazole in the Description section of the package insert.
`
`

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`NDA 21-729
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`Page 3
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`9. During a recent inspection of the Bristol Myers Squibb drug product manufacturing and release
`testing facility for this application, located at Mayaguez, Puerto Rico (CFN # 2627673), our field
`investigator conveyed deficiencies to the facility representatives. Satisfactory resolution of these
`deficiencies is required, and this site will need to be found acceptable by the F DA's Office of
`Compliance, before this application may be approved.
`
`\
`
`10. We request that you adopt the following dissolution method and specification:
`
`V Apparatus: USP Apparatus II (Paddle)
`Speed: 75 rpm
`Media: pH 4 Acetate Buffer
`Volume: 1000 mL
`
`Specification: Q NLT -— in 30 minutes
`
`11. We are granting your request for a waiver of in vivo bioequivalence studies for the 10 mg, 15 mg
`and 20 mg tablet strengths.
`
`12. We have no objections to the use of the proprietary name, Abilify Discmelt.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We
`note that you have not fulfilled the requirement. We are waiving the requirement for pediatric studies
`for this application.
`
`In addition, you must submit final printed labeling (FPL) for the drug. The labeling ‘should be identical
`in content to the attached package insert.
`
`'
`
`Please submit the final printed labeling (FPL) electronically according to the guidance for industry
`titled Providing Regulatory Submissions in Electronic Format — NDA (January 1999). Alternatively,
`you may submit 20 paper copies of the FPL as soon as it is available but no more than 30 days after it
`is printed. Please individually mount ten of the copies on'heavyweight paper or similar material.
`
`If additional information relating to the safety or effectiveness of this drug becomes available, revision
`of the labeling may be required.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock—up form, not final print. Send one copy to
`this division and two copies of both the promotional materials and the package insert(s) directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD—42
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`Within 10 days after the date of this letter, you are required to amend this application, notify us of your
`intent to file an amendment, or follow one of your other options under 21 CFR 314.] 10. If you do not
`follow one of these options, we will consider your lack of response a request to withdraw the
`
`

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`NDA 21-729
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`Page 4
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`application under 21 CFR 314.65. Any amendment should respond to all the deficiencies listed. We
`will not process a partial reply as a major amendment nor will the review clock be reactivated until all
`deficiencies have been addressed.
`
`The drug product may not be legally marketed until you have been notified in writing that
`application is approved.
`
`the
`
`If you have any questions, call Steven D. Hardeman, R.Ph., Senior Regulatory Project Manager, at
`(301) 594—5525.
`
`Sincerely,
`,
`‘
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`
`Russell Katz, MD.
`Director
`
`Division of Neuropharmacological Drug Products
`Office of Drug Evaluation 1
`Center for Drug Evaluation and Research
`
`

`

`3?
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`Page(s) Withheld
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`Trade Secret / Confidential
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`/ Draft Labeling
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`Deliberative Process
`
`Withheld Track Number: Approvable Letter #_/
`
`/
`
`I
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`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`RusSell Katz
`10/22/04 10:52:28 AM
`
`