CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-301
`
`CHEMISTRY REVIEW; S)
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`NDA 22—301 .
`
`Apriso (mesalamine)
`Extended-Release Capsules, 0.375 g
`
`Salix Pharmaceuticals, Inc.
`
`Gene W. Holbert, Ph.D.
`
`Division of Gastroenterology Products
`
`Page 1 of 69
`
`

`

`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Table of Contents
`
`Table of Contents2
`
`Chemistry Review DataSheet3
`
`The Executive Summary7
`
`1. Recommendations ......................................................................................................................7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 7
`
`'
`B. Recommendation On Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable ................................................................................................... 7
`
`II. Summary of Chemistry Assessments......................................................................................... 7
`
`A. Description of the Drug Product(s) and Drug Substance(s)............................................................. 7
`
`B. Description of How the Drug Product is Intended to be Used .................................'. ....................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ........................................................... 8
`
`III. Administrative........................................................................................................................... 8
`
`A. Reviewer’s Signature .................................................................................................................-....... 8
`
`B. EndorsementBlock....................................................... 8’
`
`Chemistry Assessment9
`
`1. Review of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body of Data...........9
`
`S DRUG SUBSTANCE [Mesalamine, Bayer AG] ............................................................................ 9
`
`P DRUG PRODUCT [Apriso (mesalamine) Extended-Release Capsules] ...................................... 14
`
`A APPENDICES .............................................................................................................................. 63
`
`R REGIONAL INFORMATION ............................'......................................................................... 63
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ..................................63
`
`A. Labeling & Package Insert ............................................................................................................. 63
`
`B. Environmental Assessment or Claim of Categorical Exclusion .................................................... 66
`
`111. List ofDeficiencies to be Communicated............................................... .................................66
`
`Appendix: Establishment Evaluation Report .................................................................................67
`
`Page 2 of 69
`
`

`

`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 22-301
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: 29-AUG-2008
`
`4. REVIEWER: Gene W. HoIbeIt Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`None
`
`‘
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission s Reviewed
`
`Original
`Amendment (BZ)
`Amendment (BC)
`Amendment (BC)
`
`Document Date
`
`21-DEC-2007
`25-JUL—2008
`25-AUG-2008
`01-OCT—2008
`
`7. NAME & ADDRESS OF APPLICANT:
`
`' Name:
`Address:
`
`Salix Pharmaceuticals, Inc.
`1700 Perimeter Park Drive
`
`Morrisville, NC 27560
`
`Representative:
`Telephone:
`
`William P. Forbes, Pharm. D.
`(919) 862-1818
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`Apriso
`Proprietary Name:
`Non-Proprietary Name (USAN/INN/BAN): Mesalamine
`Chemical Abstracts Name:
`Benzoic acid, S-amino-Z-hydroxy—
`Other'Names:
`5-Aminosalicylic acid (S-ASA)
`CAS Registry No:
`89-57—6
`Code Name/#:
`NA
`
`.
`
`Chem. Type/Submission Priority:
`
`0 Chem. Type:3
`
`Submission Priority: S
`
`Page 3 of 69
`
`

`

`
`”CHEMISTRY REVIEW: f
`
`Chemistry Review Data Sheet
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b)(2)',
`
`10. PHARMACOL. CATEGORY: Anti-inflammatory (gastrointestinal)
`
`11. DOSAGE FORM: Capsule, extended release
`
`Code: 610
`
`The formulation exhibits both delayed and extended release properties. On the advice of the
`labeling and nomenclature committee, the dosage form name “capsules, extended release”
`will be used.
`'
`
`12. STRENGTH/POTENCY: 0.3 75 g
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`_
`
`‘
`
`Code: 001
`
`14. Rx/OTC DISPENSED: LRX
`
`OTC
`
`
`
`15. SPOTS SPECIAL PRODUCTS ON-LTNE TRACKING SYSTE :
`
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT: '
`
`HM
`2
`
`0
`
`OH
`
`OH
`
`Molecular Formula: C7I-I7N03 Molecular Weight: 153.14
`
`Page 4 of 69
`
`

`

`
`
`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`i
`,
`
`II
`
`IV 2
`
`/
`
`I/
`
`I
`
`/
`/
`1
`
`/
`
`1’
`r
`l
`
`.
`' g”
`/
`/
`
`IV
`
`IV ;
`1v ;
`*
`
`H<
`
`III
`
`III
`
`I—ly—(—1
`
`“\
`
`‘w.
`
`N?”wrN‘W
`
`N...
`
`/
`
`l
`
`Adequate
`
`Adequate
`
`Adequate
`
`1
`
`Adequate
`
`/!
`
`r
`/
`/
`N\N
`/f
`f
`i
`
`w
`
`1
`
`1
`
`.
`
`l
`
`Adequate
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Com-leted
`
`25-JAN-2007
`G. Holbert
`30-DEC-2002
`G. Lunn
`8-FEB-2005 »
`B. Wu
`17-Mar-2008
`
`22-FEB-2005
`
`M. Ysern
`
`D. Gill
`18-APR—2007
`G. Holbert
`15-SEP-2000
`D. Klein
`22-APR-2002
`R. Frankewich
`07-DEC-2006
`G. Holbert
`06-DEC-04
`R. Madurawe
`
`LOA Date:
`27-JUN—2003
`,LOA Date:
`-
`lZ—OCT—2007
`
`29-AUG—2005
`LOA Date:
`
`29-AUG-2005
`LOA Date:
`29-AUG-2005
`LOA Date:
`
`LOA Date:
`11-SEP-2007
`LOA Date:
`31-JUL-2007
`LOA Date:
`31-JUL-2007
`LOA Date:
`07-AUG-2007
`
`Adequate
`
`.
`
`Adequate
`
`27-JUL-2004
`S. Po e
`27-MAY—2003
`D. Christner
`
`LOA Date:
`12-SEP-2007
`LOA Date:
`31-JUL-2007
`
`Adequate O7-DEC-2006
`G. Holbert
`
`LOA Date:
`31-JUL—2007 ‘
`
`”(4)
`
`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 “Comments”)
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need to
`be reviewed)
`
`Page 5 of 69
`
`

`

`
`a I CHEMISTRY REVIEWI." "
`
`Chemistry Review Data Sheet
`
`B. Other Documents:
`
`DOCUMENT APPLICATION NUMBER DESCRIPTION
`
`IND
`NDA '
`NDA
`
`62,113
`19-651
`21-252
`
`Mesalamine granules
`Asacol® (mesalamine tablets)
`Canasa® (mesalamine suppositories)
`
`1 8. STATUS:
`
`
`
`
`
`
`
`CONSULTS/CMC
`
`
`
`_——_
`04-AUG 2008
`__—_
`_—
`__—
`_
`
`
`
`
`
`
`Microbiology __—
`
`Page 6 of 69
`
`

`

`
`7.,..jCHEMISTRY REVIEW '
`
`Executive Summary Section
`
`The Chemistry Review for NDA 22-301
`
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA has provided sufficient CMC information to assure the identity, strength,
`purity, and quality of the drug product. All facilities involved'are in compliance with
`cGMP, and labels have adequate information as required. Therefore, from a CMC
`perspective, this NDA is recommended for “Approval”.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`None.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Apriso (mesalamine) Capsules are light blue capsules printed with the letters G and M on
`either side of a black band. Each capsule contains 0.375 g of Mesalamine USP; Inactive
`ingredients include microcrystalline cellulose, colloidal silicon dioxide, hypromellose,
`
`poly(ethy1acrylate/methyl methacrylate) —— nonoxynol 100 dispersion
`V
`--- simethicone emulsion, magnesium stearate, l:
`3 talc, triethyl citrate, titanium dioxide, aspartame,
`..—-. vanilla flavoring agent and edible black ink. With
`anhydrous citric acid, povidone
`the exception of the flavoring, film coating, and printing ink, all excipients are
`compendial. The flavoring, film coating and ink are composed of ingredients that are
`compendial and/or GRAS. The product exhibits both delayed and extended release
`properties.
`
`Apriso Capsules are manufactured by Catalent Pharma (formerly Cardinal Health),
`Winchester KY.
`I",
`
`- M4)
`
`b(4i
`
`Page 7 of 69
`
`

`

` CHEMISTRY REVIEW .
`
`Executive Summary Section
`
`33(4)
`
`_‘
`M4?
`
`The application contains 36 months of long term stability data on three registration
`
`batches manufactured by Catalent and packaged into 30 cc (4-count) and
`——- bottles.
`
`There were no significant changes in any of the lots stored at the long term, intermediate
`or accelerated condition, supporting the applicant’s proposed 36 month expiration dating
`
`periodfor any packaging configuration between 4—count and
`bottles when
`stored at 20-25°C (68-77°F) and protected from freezing.
`
`The active drug substance is mesalamine. Mesalamine. is an almost white, light grey or
`light pink powder used as a gastrointestinal anti-inflammatory agent. Several
`mesalamine formulations are approved for marketing in the US.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The recommended dose for maintenance of remission of ulcerative colitis in adults is
`
`1.5 g (4 Apriso 0.375 g capsules) once daily.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`This NDA_ provided adequate information on the raw material controls, manufacturing
`process, specifications, and container/closure. It also provided sufficient stability data to
`assure identity, strength, purity and quality of the drug product during the shelf life. The
`Office of Compliance has issued an “Acceptable” overall recommendation for all the
`facilities involved. Labels have the required information.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`Signed electronically in DFS.
`
`B. Endorsement Block
`
`Gene W. Holbert, Ph.D.
`Marie Kowblansky, Ph.D;
`
`28-OCT-2008
`28-OCT-2008
`
`Page 8 of 69
`
`

`

`(,1
`
`Page(s) Withheld
`
`\/ Trade Secret / Confidential (b4)
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`Withheld Track Number: Chemistry-
`
`I
`
`

`

`------------uu-u-u-n-u-u--------------------------—-—--------------------------------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Gene Holbert
`10/28/2008 11:49:31 AM
`CHEMIST
`
`Marie Kowblansky
`10/28/2008 01:51:35 PM
`CHEMIST
`
`

`

`Initial Quality Assessment
`'
`Branch 3
`
`Pre—Marketing Assessment Division 2
`
`0ND Division: Division of Gastroenterology Products
`NDA:
`22-301
`
`Salix Pharmaceuticals
`Applicant:
`12/31/2007
`Stamp Date:
`1/8/2008
`Received by PAL:
`2/13/2008
`Review Date:
`10/31/2008
`‘ PDUFA Date:
`
`2/13/2008
`Filing Meeting:
`Proposed Trademark:
`Established Name: mesalamine
`
`Dosage Form:
`Route of Administration:
`Indication:
`
`capsule
`oral
`ulcerative colitis
`
`”(4)
`
`P.A,L: Marie Kowblansky, PhD
`
`ONDQA Fileability:
`Comments for 74-Day Letter
`
`YES
`
`>14
`
`NO
`
`IE
`
`A. Summary
`
`M (mesalamine) Capsules is intended for maintenance of remission of ulcerative colitis in
`patients 18 years of age and older. The proposed product is a hard gelatin capsules containing
`
`0.375 mg of mesalamine in a delayed and extended release formulation, with instructions to
`administer four capsules (1.5 9) once daily?
`This product, which was studied under
`IND 62,113, is being filed by Salix as a 505(b)(2) application. Since this is a new formulation of a
`currently approved drug, this application, is classified as a Type 3 in the Chemical Classification
`Code.
`
`[1(4)
`
`Drug Substance
`
`The active drug substance. which will be manufactured by l —-———-
`COOH
`
`is mesalamine USP
`
`“(4)
`
`0H
`
`HzN
`
`
`Only limited chemistry, manufacturing, and controls information reqardina this drug substance is
`provided in the submission;
`reference is made to
`for complete CMC
`information. The proposed specification fully conforms to the USP monograph for mesalamine,
`with additional requirements for particle size f
`3‘ and microbial limits.
`
`by”
`
`

`

`Drug Product
`
`The product, which has both delayed and extended release properties, will be prepared in a
`single strength, 0.375 mg mesalamine per capsule. The capsules will be filled with release—
`controlling granules of the following composition.
`
`
`-w '
`Component
`
`
`E
`3
`
`
`Mesalairiiric
`7
`77
`Active inggdient
`‘375
`Colloidal silicon dioxide
`
`In lca . sule
`
`Standard
`
`“”—
`
`USP
`
`‘ ’
`
`'
`
`'
`
`‘
`
`"
`
`7
`
`7
`
`I;
`I!
`fl
`
`_
`
`-
`
`f/
`I
`
`j
`
`f,
`
`f
`
`‘
`
`‘
`
`fl
`
`b(4)
`
`‘7
`
`"- -_.
`l
`
`,
`~
`_
`‘ . ,_.._
`/
`1'
`/
`— 1/
`x!
`:1
`.1
`I,
`if
`
`.
`
`,1"
`
`I
`
`[If
`— [Z —-
`
`--
`
`‘
`
`stalline cellulose
`Micros
`
`' Simethicone
`
`.,..
`emulsion.
`
`
`Poly(elhylacrylato-
`- methylmethacrylaio) ~----
`
`nonoxvnol 100 dispersion
`va'omellose .’ """-
`"‘ '
`
`.
`
`m
`
`W
`
`Ma_ esium stearate
`
`Triethvl citrate
`
`
`_——-
`H uromellose 6581-150
`Uralc
`
`Povidone "o“
`
`Vanilla flavoring
`
`Hypromellose
`.
`
`I
`
`V A
`
`
`
`Light blue, opaque “00” hard
`gelatin capsule shell with
`'
`identifier mark
`
`
`
`
`5
`..I
`
`.-'
`
`

`

`A|| excipients in the formulation are‘compendial, with the exception of the vanilla flavoring and
`
`poly(ethylacrylate—methylmethacrylate) -- nonoxynol 100 dispersion
`DMFs
`are referenced for these two excipients.
`-
`
`The granule formulation is composed of ; I"
`
`_i The applicant explains that the current granule formulation was developed by Dr. Falk
`Pharma, which markets the product in Europe as a sachet product where the granules are meant
`to be swallowed whole, without a capsule. When Salix acquired the product, they did not want to
`change it fr“
`.1
`
`The product will be manufactured by Catalent Pharma Solutions and will be of the same
`composition as the batches used in the Phase 3 clinical studies. The manufacturing process
`l”
`
`i"
`
`i"
`
`[3(4)
`
`13(4)
`
`M4)
`
`[1(4)
`
`The proposed specification appears reasonable, conforming to lCH guidelines with respect to
`impurity limits, and the acceptance criteria for Stage 2 of the dissolution test (conducted in pH 6.8
`buffer) are typical for an extended release product.
`It should be noted, however. that in several
`sections of the submission the acceptance criterion for unidentified impurities is listed as NMT
`-~ as listed above, but the batch analysis data list NMT -" as the acceptance criterion.
`
`11(4)
`
`

`

`The applicant provides 24 months of 25°C stability data and 6 months of accelerated stabilitv
`
`data for product packaged in 30 cc HDPE bottles (4 capsules) and: ~— HDPE bottles ——
`with induction seals. The applicant considers the submitted stability studies as a
`bracketing approach, requesting a —---
`expiry for 4 to —- capsules packaged in any size
`HDPE bottle ranging from 30 to 300 cc.
`
`for submitting an
`Salix appropriately. claims categorical exclusion from the requirement
`environmental assessment on the basis that the estimated concentration of mesalamine at the
`point of entry into the aquatic environment will be below 1~part per billion (the estimated
`concentration is m I).
`‘
`
`Inspection reguests for the facilities involved in the manufacture of the drug substance and drug
`product have been entered into EES. (See appended list.)
`
`11(4)
`
`M4)
`
`B. Critical issues for review
`
`Based on this initial assessment. the following issues will need particular attention during the full
`review of this NDA:
`
`-- For the two non-compendial excipients, poly(ethylacrylate—methylmethacrylate) -- nonoxynol
`100 dispersion w and vanilla flavoring, confirmation should be obtained from the
`Clinical Toxicology reviewer that these are safe at the proposed levels
`
`:3
`-- The drug product specification speCIt”es 3 f
`E
`
`l’
`..L
`
`3. Yet, the batch analysis data show two of the batches containing...I
`
`-- In all listings of the drug product. specification the acceptance criterion for unidentified impurities
`is given as NMT -"
`However,
`in the batch analysis data the unidentified impurities
`acceptance criterion is listed as NMT w This should be clarified and evaluated in terms _of the
`2 mg ICH identification threshold for a daily dose of 1.5 grams per day. The - exceeds the
`ICH recommendation.
`
`-- The applicant has used a bracketing approach to stabilitv data providinq stabilitv data for a 30
`cc and --'
`container,
`‘2:
`
`'7
`
`C. Comments for 74-Day Letter— None '
`
`D. Recommendation: From the CIVIC perspective, this application should be filed
`
`Marie Kowblansky, PhD
`Pharmaceutical Assessment Lead
`
`Moo-Jhong Rhee, PhD
`Branch Chief
`
`2/14/2008
`Date
`
`2/14/2008
`Date
`
`33(4)
`
`0(4)
`
`31(4)
`
`M4)
`
`

`

`no
`
`NDA 22-301
`
`Manufacturing Sites
`
`Drug Substance
`
`$2321gciittl‘Manufaemrlng and
`
`Contact Person
`
`Site finction
`Drug substance
`manufacturing
`Particle size regulatory
`release testing
`Stability testing
`
`Labeler code number: 01 1014
`
`Catalent' Pharma Solutions
`(formerly Cardinal Health)
`1 100 Enterprise Drive
`.
`Winchester, KY 40391
`
`Site registration number: 1528607
`
`Testing for regulatory
`release (all attributes
`except particle size)
`
`Contact Name: Beth Rhodes
`Title: Director, Quality Systems
`Telephone: 859—745-8126
`Email: beth.rltodes@catalent.com
`
`Drug Product
`
`Contact Person
`
`Commercial Manufacturing and
`Site Function
`Testln Sites
`Drug product manufacturing
`Catalent Pharma Solutions
`Contact Name: Beth Rhodes
`Title: Director, Quality Systems
`Testing for regulatory release
`(formerly Cardinal Health)
`
`
`
`
`Telephone: 859-745-8126
`Stability testing
`I 100 Enterprise Drive
`
`
`
`
`Winchester, KY 40391
`Email: bethrhodes@catalcnt.com
`
`
`
` Site registration number: 1528607
`Labeler code number: 01 MM
`Catelent Pharma Solutions
`Contact Name: John Ronn
`
`Packaging
`
`
`
`
`(formerly Cardinal Health)
`Title: Sr. Regulatory Affairs Specialist
`3001 Red Lion Road
`
`
`Telephone (215) 613-3580
`
`
`Philadelphia, PA 19114
`
`Email: john.ronn@catalent.com
`
`
` Site registration number: 2530802
`
`bluebi- code number: 011014
`
`
`
`Packaging
`
`
`
`Stability testing
`
`
`
`

`

`Filing Checklists (NDA 22-301)
`A. Administrative Checklists;
`
`
`
`
`_ Comments
`-—-__
`
`-__-_
`-__
`
`
`
`
`
`Has an environmental assessment report or categorical
`exclusion been rovided?
`
`
`
`
`
`B. Technical Checklists;
`1. Drug Substance
`
`Does the section contain synthetic scheme with in-process
`.arameters?
`Does the section contain structural elucidation data?
`Does the section contain 5 ecifications?
`Does the section contain information on im-urities?
`Does the section contain validation data for anal
`ical methods?
`Does the section contain container and closure information?
`Does the section contain stabili
`data?
`
`Does the section contain tradename and established name?
`
`Does the section contain manufacturing process with in-process
`controls?
`controls of exci ients?
`Does the section contain uali
`Does the section contain information on com osition?
`Does the section contain s ecifications?
`
`Does the section contain information on de_radation nroducts?
`Does the section contain validation data for anal
`ical methods?
`Does the section contain information on container and closure
`3 stems?
`
`Does the section contain stability data with a proposed
`ex - iration date?
`Does the section contain information on labels of container and
`cartons?
`
`Has all information requested during the IND phases, and at the I
`
`re-NDA meetins been included?
`Is a team review recommended?
`
`Are DMFs adeuatel
`referenced?
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Marie Kowblansky
`2/21/2008 04:50:03 PM
`CHEMIST
`
`Moo—Jhong Rhee
`2/21/2008 04:51:45 PM
`CHEMIST
`
`Chief, Branch III
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`