CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICA TION NUMBER:
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`21-450
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`CHEMISTRY REVIEW! S!
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`NDA 21-450
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`Zomig® (zolmitriptan) Nasal Spray
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`AstraZeneca Pharmaceuticals LP as U.S. agent for:
`IPR Pharmaceuticals
`
`Martha R. Heimann, Ph.D.
`Division of Neuropharmacological Drug Products
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`MPEERS THIS WAY
`ON UREGHML
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`Table of Contents
`
`Chemistry Review Data Sheet...... ................................ . ........................................................................ 4
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`The Executive Summary ....................................................................................................................... 8
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`1. Recommendations ................................................................................................................................ 8
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`A. Recommendation and Conclusion on Approvability .................................................................................. 8
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`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, andfor Risk Management
`Steps, if Approvabie ................................................................................................................................... 8
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`II. Summary of Chemistry Assessments ................................................................................................. 8
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`A. Description of the Drug Product(s) and Drug Substance ............................................................................ 8
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`B. Description of How the Drug Product is Intended to be Used .................................................................. 10
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`C. Basis for Approvability or Not—Approval Recommendation .................................................................... 10
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`III. Administrative ................................................................................................................................. l l
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`A. Reviewer’s Signature ................................................................................................................................ 1 1
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`B. Endorsement Block ................................................................................................................................... 11
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`C. CC Block ................................................................................................................................................... 1 1
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`Chemistry Assessment
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`..........................
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`.............................................. ......
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`........................... 12
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`1. Review of Common Technical Document-Quality (CTD-Q) Module 3.2: Body of Data ................ 12
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`S DRUG SUBSTANCE .............................................................................................................................. 12
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`8.1 General Information ....................................................................................................................................... 12
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`5.2 Manufacture ................................................................................................................................................... 12
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`8.3 Characterization ............................................................................................................................................. 13
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`8.4 Control of Drug Substance............................................................................................................................. 13
`8.5 Reference Standards or Materials .............................................................................................................
`15
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`8.6 Container Closure System .............................................................................................................................. 15
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`3.7
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`Stability .......................................................................................................................................................... 15
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`P DRUG PRODUCT ................................................................................................................................... 16
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`P.1 Description and Composition of the Drug Product ........................................................................................ 16
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`Pharmaceutical Development ........................................................................................................................ 20
`P2
`1’3 Manufacture ................................................................................................................................................... 29
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`P.4 Control of Excipients ..................................................................................................................................... 34
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`P5 Control of Drug Product ................................................................................................................................ 36
`P.6 Reference Standards or Materials .................................................................................................................. 48
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`R7 Container Closure System .............................................................................................................................. 48
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`RS
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`Stability .......................................................................................................................................................... 51
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`A.l Facilities and Equipment (biotech only) .......................................................................................................... 57
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`A2 Adventitious Agents Safety Evaluation ........................................................................................................... 57
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`A3 Novel Excipients.............................................................................................................................................. 57
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`R REGIONAL INFORMATION .................................................................................................................. 57
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`R1 Executed Batch Records ................................................................................................................................... 57
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`R2 Comparability Protocols ................................................................................................................................... 57
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`R3 Methods Validation Package ............................................................................................................................ 58
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`II. Review of Common Technical Document-Quality (CTD-Q) Module 1 ......................................... 59
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`A. Labeling & Package Insert ....................................................................................................................... 59
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`B. Environmental Assessment or Claim of Categorical Exclusion................................................................ 59
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`111. List of Deficiencies to be Communicated ....................................................................................... 60
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`APPEARS THIS; 2%"?
`0H GRIGIHAL
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`iii
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`Chemistry Review Data Sheet
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`. NDA #: 21-450
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`. REVIEW #: 1
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`REVIEW DATE: 09-DEC—2002
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`. REVIEWER: Martha R. Heimann, Ph.D.
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`. PREVIOUS DOCUMENTS:(This is review #1.)
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`. SUBMISSION(S) BEING REVIEWED:
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`Submission; 5! Reviewed
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`Document Date
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`Original NDA
`
`CMC Update ‘
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`Revised Package Insert
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`06-MAR-2002
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`27-JUN—2002
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`22-NOV-2002
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`. NAME and ADDRESS OF APPLICANT:
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`Name:
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`Address:
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`IPR Pharmaceuticals, Inc
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`P.O. Box 1967
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`Carolina, PR 00984-1967
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`Representative:
`
`Kevin McKenna, Executive Director-Regulatory Affairs
`AstraZeneca Pharmaceuticals LP
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`1800 Concord Pike, PO. Box 8355
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`Telephone:
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`(302)886-2742
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`. DRUG PRODUCT NAME/CODE/TYPE:
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`a) Proprietary Name: Zomig®
`b) Non-Proprietary Name (U SAN): zolmitriptan
`c) Code Name/#: 31 {€90
`d) Chem. Type/Submission Priority:
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`0 Chem. Type: 3
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`0 Submission Priority: S
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`Page 4 of 64
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`Chemistry Review Data Sheet
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`9. LEGAL BASIS FOR SUBMISSION: N/A
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`10. PHARMACOLOGICAL CATEGORY:
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`Zolmitriptan is a selective 5-hydroxytryptamine IB/lD (5-HTIB/m) receptor agonist intended for the
`acute treatment of migraine.
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`ll. DOSAGE FORM: Nasal Spray
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`12. STRENGTH/POTENCY:
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`
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`5 mg per single dose unit
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`‘13. ROUTE 0F ADMINISTRATION: Nasal
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`14. Rx/OTC DISPENSED: LRX
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`OTC
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`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
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`SPOTS product — Form Completed
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`X Not a SPOTS product
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`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
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`Structural Formula:
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`r
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`?”3
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`O=<WH3
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`Chemical Name:
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`» (S)—4-{[3-[2-(Dimethylamino)ethyl]- 1H-indol-S-yl]methyl}-oxazolidinone
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`Molecular Formula: C16H21N302
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`Molecular Weight: 287.36
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`APPEARS THIS WAY
`0N 8R1: mm.
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`Page 5 of 64
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`Chemistry Review Data Sheet
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`17. RELATED/SUPPORTING DOCUMENTS:
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`A. DMFs:
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`DMF # TYPE HOLDER
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`ITEM
`REFERENCED
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`I
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`CODE
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`STATUS
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`2 DATE REVIEW
`COMPLETED
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`COMMENTS
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`Adequate
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`22-APR-2002 by
`Y. Yang
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`Adequate
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`16-FEB-2000 by
`L. Zhou
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`--
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`' Action codes for DMF Table:
`l — DMF Reviewed.
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`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 w Authority to reference not granted
`6 — DMF not available
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`7 — Other (explain under "Comments")
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`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need to be
`reviewed)
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`DESCRIPTION
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`Cross-referenced for drug
`substance CMC information
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`B. Other Documents:
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`DOCUMENT
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`Zomig immediate release tablets N20-768
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`APPLICATION NUMBER
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`
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`APPEMS THlS ‘PJAY
`ON GfiifiiHAL
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`Page 6 of 64
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`18. STATUS:
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`Chemistry Review Data Sheet
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`Biopharm
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`Not Approvable
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`07-Nov—2002,
`02-DEC-2002
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`A. Jackson
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`CONSULTSI CMC
`RELATED REVIEWS RECOMMENDATION DATE
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`REVIEWER
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`I Pharm/I‘ox issues related to qualification of degradants and specification limits were discussed with
`Dr. Fossum
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`WPEARS ””3 WAY
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`0N OREGENAL
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`Page 7 of 64
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`The Chemistry Review for NDA 21-450
`_.
`in"?!
`-.~';
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`The Executive Summary
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`1. Recommendations
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`A. Recommendation and Conclusion on Approvability
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`Approval of NDA 21-450 is recommended from a CMC perspective.
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`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
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`No Phase 4 commitments or risk management steps are indicated from a CMC perspective.
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`II. Summary of Chemistry Assessments
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`A. Description of the Drug Product(s) and Drug Substance
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`Zomig® NS (zolmitriptan) Nasal Spray will be marketed for acute treatment of migraine
`headache as a unit dose nasal spray device which will deliver "—_"“-""‘—'_‘
`_ 5 mg of
`zolmitriptan in a 100 uL (0.1 mL), non-preserved aqueous solution. The product is not labeled
`as sterile. The nasal spray solution also contains citric acid and dibasic sodium phosphate. The
`solution is contained in a Type 1 clear glass vial with rubber stopper, which is thenassembled
`into the nasal spray device.
`
`The drug is administered used by removing the protective cap, placing the actuator into the
`nostril and pressing the thumb push, which breaks the break ring and actuates the device. Upon
`actuation, the rubber stopper is pierced and forced downward by the needle jig. The contents of
`the vial are forced up through the needle and out of the nozzle via the spray chamber. Refer to
`the figure on the following page for a cross-section view of the device. Spray characteristics
`(geometry and droplet size distribution) are determined by the size and shape of the spray
`chamber, the size of the needle orifice and actuation force.
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`Page 8 of 64
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`Executive Summary Section
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`Cross Section View of Zomig NS Unit Dose Nasal Spray Device
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`
`
`111‘71,
`s)»
`
`Ill’l’lllllll.
`
`
`a. 'Bill/Ill
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`'II
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`7 ~
`v
`' n’ ’A'
`: War.
`
`‘
`’3
`’5’ ‘
`: he 1:5 g
`l a}
`In;I
`i
`‘
`I
`W h
`i a:
`as:
`
`
`
`a
`l
`\
`\"f‘ \ ‘V‘l
`i/w‘yh
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`
`
`
`
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`\\\\\\\\\\\‘
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`Thumb push
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`4
`
`
`
`I
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`The active ingredient of Zornig® NS, zolmitriptan, is currently marketed as Zomig Tablets
`(immediate release) under NDA 20-768 and Zomig ZMT (orally disintegrating tablets) under
`NDA 21-231. NDA 20-768 is cross-referenced for information regarding manufacture,
`characterization and control of the bulk drug substance.
`
`--————-————-—————_______..————-—————— MW is 287.36). It
`Zoimitriptan
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`is a basic compound
`‘ and solubility increases as solution pH decreases. In solution,
`the drug substance susceptible to both hydrolytic and oxidative degradation, especially at pH
`equal to or greater than“. Physical and chemical parameters critical to the nasal spray
`formulation include solubility in aqueous solutions and stability in solution. lntranasal delivery
`of the highest dose, 5 mg, in a suitable volume requires drug solubility greater than . f
`Use of as citric acid] dibasic sodium phosphate based buffer system is necessary to achieve the
`required solubility while maintaining a solution pH (5) similar to that of human nasal mucosa.
`This target pH minimizes, but does not eliminate, product degradation.
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`Page 9 of 64
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`Protection cap
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`Actuator
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`Needle jig/Spray chamber
`Needle
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`Viol
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`w
`Wall holder
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`‘.
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`'
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`I
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`VU
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`

`

` . MISTRY REVIEW_
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`
`Executive Summary Section
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`Although the productIS not labeled as
`_________*_____~___‘
`to ensure absence of microorganisms at time of manufacture.
`Based on process development studies, a number of parameters have been identified as critical
`
`to ensuring product quality.
`
`
`
`W Additional process
`parameters identified as critical include solution pH during compounding and vial fill weights
`
`The proposed commercial product and process differs from the product used in the single
`efficacy study (311CIL/0077)in two respects.
`,____.__——————--—-—--———~
`.__—a—-——————--——-—-———-——- Additionally, although the internal mechanism of
`the proposed commercial nasal spray device13 identical to the clinical study device, an external
`'break ring" is incorporated into the commercial device. The sponsor has provided comparative
`in-vitro data in support bio-waiver request. The Office of Clinical Pharmacology and
`Biopharmaceutics (OCPB) reviewer, A. Jackson indicates in his review that a number of device
`equivalence criteria were not met.
`
`B. Description of How the Drug Product is Intended to be Used
`
`_.____
`The product will be marketed in cartons containing six 5 mg unit dose devices.
`
`l:1
`¢_.
`--
`h
`A
`...—-———_.._._.——-—h
`_._—
`
`:l
`
`
`_ —'5. mg administered intranasally “——
`_
`-
`7
`The recommended doses are
`, —_,___._——-—-——-——_——-———————-—__._______.
`.If the headache
`returns, the dose may be repeated after 2 hours. Total dose should not exceed 10 mg over 24
`hours.
`
`Based on stability. data provided in the application, an expiration dating period of 24 months,
`when stored at controlled room temperature (20 - 25°C) is established for the 5 mg, ‘
`._———_——
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`
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`C. Basis for Approvability or Not-Approval Recommendation
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`From a CMC perspective, the sponsor has provided adequate documentation of the composition
`of the proposed drug products, control of ingredients, the manufacturing process, control of
`critical manufacturing steps and control of the finished product. Dr. Sweeney's review of the
`microbiology controls did not identify any deficiencies that would affect approvability of the
`NDA. Adequate validation data to support the proposed regulatory methods was provided.
`Stability data are adequate to support the proposed expiry periods. Establishment inspections
`have been completed and an overall acceptable compliance recommendation was received.
`[Refer to Attachment 3.]
`
`Although it does not affect the approvability of the current application, an error was noted in
`the drug substance specification, which was approved under NDA 20-768. The comment on
`page 60 of this review should be relayed to the sponsor.
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`Page 10 of 64
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`Executive Summary Section
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`III. Administrative
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`i
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`A. Reviewer’s Signature
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`See electronic signatures in Divisicn file System (DFS).
`B. Endorsement Block
`I
`‘
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`See electronic signatures in DFS.
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`C. CC Block
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`See DFS.
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`Page 11 of 64
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`53 Page(s) Withheld
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`/ § 552(b)(4) Trade Secret / Confidential
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`§ 552(b)(5) Deliberative Process
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`§ 552(b)(5) Draft Labeling
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`