CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TION NUMBER:
`
`'
`
`' 50-805
`
`CHEMISTRY REVIEWg S!
`
`

`

` ' CHEMISTRY REVIEW ‘
`
`NDA 50-805
`
`Oracea (Doxycycline), capsules 40mg
`CollaGenex Pharmaceuticals, Inc._
`
`Division of Dermatology and Dental Products
`
`Zhengfang Ge, Ph.D.
`
`Branch 111, Division of Pre-Marketing Assessment 11
`Office of New Drug Quality Assessment
`
`

`

`CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents ...........
`
`................................. . ........................................ . ............ 2
`
`Chemistry Review Data Sheet...................................................... . ..........................3
`
`The Executive Summary
`
`............................................................. . .......................8
`
`1. Recommendations .............................................. ......................................................................... 8
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 8
`1. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/0r Risk
`Management Steps, if Approvable ................................................................................................... 8
`
`II. Summary of Chemistry Assessments ..............
`
`......................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 8
`
`B. Description of How the Drug Product is Intended to be Used........................................................... 9
`
`C. Basis for Approvability or Not—Approval Recommendation ............................................................ 9
`
`III. Administrative........... .............................................................................................................. 10
`
`A. Reviewer’s Signature ...............................................'. ...................................................................... 10
`
`B. Endorsement Block ......................................................................................................................... 10
`
`C. CC Block ........................................................................................................................................ 10
`
`Chemistry Assessment
`
`.............................................................. ................ 1 1
`
`I. Review Of Common Technical Document--Quality (Ctd--Q) Module 3.2: Body Of Data ....... 11
`
`S DRUG SUBSTANCE .
`f
`_
`”.5.............................................................. 11
`P DRUG PRODUCT ' MW ............................................................... 14
`
`A APPENDICES .............................................................................................................................. 43
`
`R REGIONAL INFORMATION ..................................................................................................... 43
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ..................................43
`
`A. Labeling & Package Insert ............................................................................................................ 43
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................... 46
`
`III.
`
`List Of Deficiencies To Be Communicated ....................................................................... 46
`
`

`

` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA # 50-805
`
`2. REVIEW # 1
`
`3. REVIEW DATE: May 25, 2006
`
`I 4. REVIEWER: Zhengfang Ge
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`None
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission( 5) Reviewed
`
`Original submission
`
`Document Date
`
`August 1’ 2005
`
`7. NAME & ADDIUBSS OF APPLICANT:
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`COLLAGENEX PHARMACEUTICALS, INC
`
`41 UanCI‘Slty Drlve, Sulte 200, Newtown, PA
`18940
`
`215—579-7388
`
`Page 3 of 54
`
`

`

`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Oracea
`b) Non-Proprietary Name (USAN): Doxycycline
`0) CAS No: 17086-28-1
`(1) Code Name/# (ONDQA only): COL101, MA64
`e) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 5
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: This application was filed under the
`provisions of section 505(b)(1) of Federal Food, Drug and Cosmetic act and 21
`CFR 314.50.
`
`10. PHARMACOL. CATEGORY: T
`rosacea
`
`
`
`inflammatory lesions in patients with
`
`11. DOSAGE FORM: Capsules
`
`12. STRENGTH/POTENCY: 40 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. RX/OTC DISPENSED:
`
`X RX
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`
`X
`Not a SPOTS product
`
`Page 4 of 54
`
`

`

` I CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`16.CHEMICAL NAB/IE, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Name:
`
`2-Naphthacencecarboxamide, 4-Dimethylamino- 1 ,4,4a,5,5a,6,l 1,12a-octahydro-
`3 ,5 ,10,12,12a-pentahydroxy-6,methyl-1,1 1-dioxo-, [4S—(40L, 4aa, 50L, Saa, 6a,12a(x)]-,
`monohydrate
`
`Molecular Formula: C22H24N203 -H20
`
`
`
`CONH2
`
`.HZO
`
`Molecular Weight: 462.46
`
`17. RELATED/ SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
`DATE
`
`COMMENTS
`CgEhZ/IEEEVT
`STATUS2
`REFéghfiCED CODE'
`HOLDER
`DEE/[F g;
`ED
`Reviewed for ANDA
`
`65-285,
`1-Sep- 2005
`Adequate
`
`'
`Deoxycycline tablets
`.
`
`.
`
`l
`
`,
`
`Adequate
`
`I
`
`Adequate
`
`2003
`
`23—Sep-
`2005
`
`Dr. D. Klein for NDA
`.
`.
`
`
`
`27-Jul-2004 | Dr. 8. Pope for NDA
`
`
`
`Adequate
`
`Page 5 of 54
`
`
`
`
`Rev1ewed for this
`3_Apr—2006
`} Adequate
`NDA
`
`
`30—Dec-
`2002 and
`
`_
`Dr. George Lunn and
`
`_
`1l-June—
`Dr.ArtShaw
`
`
`
`

`

`
`» CHEMISTRY REVIEW
`_
`‘
`
`Chemistry Review Data Sheet
`
`_|
`|.,-,_Qo_rp_l____j_ J._
`1
`21-633
`02-Sep-
`Adequate
`Dr. B. Wu for ANDA
`
`_
`2003
`65-061
`
`Dr. R. Frankewich for
`'
`V
`NDA 21—882
`07—Jul-2005
`, Adequate
`
`
`N/A
`
`DMF is not available.
`Since it is a blister
`
`component for oral
`solid dosage form, no
`DMF review is
`
`
`
`
`
`
`
`I.
`L
`
`conducted based on
`.
`
`the policy
`Zhengfang Ge,
`_i—
`3-May—2006
`Reviewed for this
`NDA
`
`Adequate
`
`_I
`
`Dr. G. Kang Reviewed
`19-Sep—
`for ANDA 75-588
`2002
`. Adequate
`
`
`IAction. codes for DMF Table:
`1 ~ DMF Reviewed.
`'
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`'
`
`B. Other Documents:
`
`
`DOCUMENT
`APPLICATION NUMBER
`I
`DESCRIPTION
`
`BOP-2 meeting minutes
`IND 67,833
`3—May-2004
`
`Amendment (NOOOBC)
`|EA50305
`10-Feb-2006
`
`Amendment (NOOOC)
`NDA50,805
`17-Apr—2006
`Amendment
`NDA50,805
`15-May-2006
`Amendment
`NDA50,805
`l 16—May-2006
`
`
`
`
`]
`J
`
`.
`
`Page 6 of 54
`
`

`

`
`
`Chemistry Review Data Sheet
`
`18. STATUS:
`
`
`
`ONDQA:
`CONSULTS/ CMC
`
`
`
`RECOMMENDATION
`DATE
`REVIEWER
`
`
`—'_
`Not Applicable
`Acceptable
`9-Feb-2006
`EER report attached in section IV
`
`
`of this review
`
`
`Pharm/Tox
`Not Applicable
`Biopharm
`Acceptable, see review
`16-May-2006 Dr. Abi Adebowale
`
`for dissolution
`
`Not Applicable
`1
`To be submitted post
`
`approval
`See review notes for
`
`
`
`15-Mar-2006
`
`Kristina Arnwine
`
`
`
`RELATED
`REVIEWS
`Biometrics
`'
`EES
`
`
`
`LNC
`
`Methods Validation
`
`DMETS
`
` EA
`
`'
`
`
`
`Not applicable ,
`
`
`
`labeling comments
`_’_
`See review notes
`|_Microbiology
`
`Page 7 of 54
`
`

`

` EMSFRY REVIEW TEMPLA
`
`Chemistry Assessment Section
`
`The Chemistry Review for NDA 50-805
`
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`Based on the CMC review and agreement on the labeling between the sponsor and the
`Agency, this NDA may be approved. A final review for the labeling mock—up based on
`the agreement of the labeling modification will be performed andadded as an
`addendum to this review. 77
`
`1. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`None
`
`11. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug substance is doxycycline, USP. Doxycycline has 6 chiral centers with a
`molecular formula C22H24N203 -H20 and the molecular weight 462.46. Doxycycline
`appears in light yellow to pale yellow crystalline powder. It is slightly soluble in water.
`The pH value for doxycycline (1% w/v suspension in water) is V'— The .1
`.
`manufacturer c
`i
`i
`
`The drug product contains two types of doxycycline beads that together provide a dose
`equivalent to 40 mg of anhydrous doxycycline. The two types of doxycycline beads are
`75% immediate—release (IR) beads and 25% delayed--release (DR) beads. The DR
`
`The
`beads are made of IR beads coated with a
`‘
`meflwfi.
`IR and DR beads are filled into a beige hard gelatin capsule shell. The drug product is
`packaged inf”. .
`, .16 with 100 capsules and 30 capsules, and in blister packages for
`physician samples. The sponsor is marketing the drug product for the bottle of 30
`capsules.
`-
`
`The sponsor briefly summarized pharmaceutical develo ment in this section. The
`development of this drug product is based on Periostat
`, an approved immediate
`release dosage form. The critical steps of the manufacturing process include
`
`Page 8 of 54
`
`

`

`
`_
`.. MISTRY REVIEW TEMPLgA ,
`
`Chemistry Assessment Section
`
`W' Process control data from three
`primary registration batches are provided in the executed product batch records.
`Specifications for intermediates (IR and DR beads), and drug products are provided.
`The drug product specification include appearance, identification, assay, content
`“F,—
`uniformity, loss on dry and dissolution, The dissolution specification "7'
`.. and
`at 2 hours and~—:-
`t 4 hours) originally proposed by the sponsor is too broad at 2
`hours based on the test results and dissolution profiles. The sponsor agreed to revise
`the dissolution specification to «r
`and ‘2" at 2 hours and \— 70 at 4 hrs.
`
`The sponsor provided 18 month stability data under 30°C/65%RH and 6 month stability
`data under 40°C/75%RH for drug products packaged in bottles of 30 capsules and 100
`capsules. The sponsor also provided 12 month stability data under 30°C/65%RH and 6
`month stability data under 40°C/75%RH for the drug products packaged in blister.
`Based on the current stability results, 24 months expiration date of the bottled drug
`products and 18 month expiration date for the blister packaged drug product are
`recommended. The recommendation of the expiration for the drug products was
`accepted by the sponsor.
`
`,:/-— for the established name.
`The sponsor proposed to use “doxycycline
`However, doxycycline, USP which already ineludes _ _/_-—— , should be used in
`
`the established name. The sponsor also proposed to use ‘
`capsules”
`for the dosage form. However, the PK profile of the drug product is similar to the
`
`commercially available immediate-release capsules, therefore, the ‘
`,
`should not be used. After several teleconferences with the sponsor, the sponsor agreed
`to remove “ M ,’ and “ "M from the labeling. A line of “30 mg
`immediate-release beads and 10mg delayed-release beads” will be added following the
`line. of dose strength.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The drug product is indicated for the treatment of the papule and pustule component of
`rosacea in adult patients.
`
`The drug product (beige opaque capsule printed with CGPI 40) contains doxycycline,
`USP in an amount equivalent to 40 mg of anhydrous doxycycline. One capsule (40mg)
`should be administered once daily in the morning on an empty stomach, preferably at
`least one hour prior to or two hours after meals.
`
`C. Basis for Approvability orNot—Approval Recommendation
`
`The sponsor addressed CMC issues in the NDA submission and amendments for
`the drug substance and drug product including components/composition,
`manufacturing process and process control, specifications and stability data. Pre-
`approval inspection concluded that all manufacturing, testing and packaging
`facilities were acceptable. After several teleconferences with the sponsor, the
`
`Page 9 of 54
`
`

`

`
`MISTRY REVIEW TEMP-mi;
`
`Chemistry Assessment Section
`
`‘ and ‘ —-——'—""‘
`....—-—-
`sponsor and the agency agreed on removing ‘
`-/. from the labeling. A line of “30 mg immediate-release beads and 10mg
`delayed-release beads” will be added following the line of dose strength. From the
`CMC point of View, this NDA can be approved. The final labeling mock-up based
`on the agreement between the sponsor and the Agency will be reviewed in an
`addendum to this review.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`In DFS
`
`B. Endorsement Block
`
`Chemist: Zhengfang Ge
`Chemistry Branch Chief: Moo—Jhong Rhee
`ProjectManager: Shalini Jain
`
`C. CC Block
`
`Page 10 of 54
`
`

`

`I
`
`AM Page(s) Withheld
`
`/ Trade Secret /‘C0infidentia1
`
`Draft Labeling
`
`Deliberative Process-
`
`-‘
`
`,Withheld Track Number: Chemistry— 10;» it
`
`-
`
`I
`
`