CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205103Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`M—_
`
` tam-m
`QUALITY ASSESSMENT
`
`Recommendation:
`
`This 505(b)(2) application is recommended for Approval from the OPQ perspective with
`expiration dating period of 36 months.
`
`NDA 205103 Resubmission)
`Review #3
`
`Drug Name/Dosage
`Form
`
`Strenth
`Route of
`Administration
`
`Rx/OTC Dis uensed
`
`YospralaTM (aspirin and omeprazole) delayed-release tablets
`
`81 m_ or 325 m_ .
`Oral
`
`irin/ 40 m_ omerazole
`
`A licant
`
`alez Pharmaceuticals R&D Inc.
`
`US agent, if applicable
`
`A
`
`SUBMISSION(S)
`REVIEWED
`
`DOCUMENT
`DATE
`
`DISCIPLINE(S) AFFECTED
`
`
`
`
`A“ 01’ ' diSCilineS
`
`Dru- Substance/Dru Product
`
`Dru- Product
`
`Drug Substance
`
`Dru- Product
`
`1mm
`
`29-Jun-2016
`
`Labeling
`
`Review Team
`
`DISCIPLINE
`
`REVIEWER
`
`BRANCH/DIVISION
`
`Drug Substance
`
`Xavier Ysern, Ph.D.
`
`Drug Product
`
`Zhengfang Ge, Ph.D.
`
`Jingbo Xiao, Ph.D.
`
`Microbiology
`
`Jingbo Xiao, Ph.D.
`
`OMPT/CDER/OPQ/ONDP/D
`ND API/NDBII
`
`OMPT/CDER/OPQ/ONDP/D
`ND PII/BV
`
`OMPT/CDER/OPQ/OPF/DIA/
`IA/BII
`
`OMPT/CDER/OPQ/OPF/DIA/
`IA/BII
`
`Facility
`
`Christina Capacci-Daniel, OMPT/CDER/OPQ/OPF/DIA/
`PhD.
`IA/BII
`
`Bioharmaceutics
`
`Hanson Chen, Ph.D.
`
`CDER/OP 0 /ONDP/DB 11
`
`Regulatory Business
`Process Mana er
`
`Truong Quach, Phar. D.
`
`OMPT/CDER/OPQ/OPRO/DR
`BPMI/RBPMBI
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 1 of 53
`
`Effective Date: 18 Feb 2016
`
`

`

`
`
`
`Application Technical Lead
`
`Danuta Gromek-Woods,
`Ph.D.
`
`OMPT/CDER/OPQ/ONDP/D
`NDPII/BV
`
`(Waui‘A’ unnu.
`
`QUALITY ASSESSMENT u" Jun“... an. ("h/r
`
`
`
`
`
`
`(OTR
`Laborato
`ORA Lead
`
`NA
`Paul Perdue Jr.
`
`NA
`OGROP/ORA/OO/OMPTO/D
`MPTPO/MDTP
`
`Environmental Analysis
`EA
`
`NA
`NA
`
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 2 of 53
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`
`Item
`Referenced
`
`
`
`
`(m4) Type II
`m Adequate Last review
`Drug
`
`dated 07-Jun-
`substance in
`
`
`2016
`NDA 205103
`
`
`
`
`
`Type II
`
`Type II
`
`
`Adequate
`
`
`
`Adequate
`
`
`
`W" (DMF
`(m4)
`
`
`
`
`last review
`Used to
`dated 03—
`manufacture
`
`
`May-2016
`
`
`
`
`
`
`last review
`Drug
`dated 24-Feb-
`substance in
`
`
`NDA 205103
`2016
`
`
`
`
`
`B. Other Documents: IND, RLD, or sister aplications
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`
`
`DESCRIPTION
`
`
`
`_ 78747 _
`
`
`
`
`2. CONSULTS
`
`DISCIPLINE
`
`
`
`
`STATUS RECOMMENDATION DATE REVIEWER
`
`
`
`
`OPQ—XOPQ-TEM-0001v03
`
`Page 3 of 53
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`Proposed Indication(s) including YOSPRALA is a combination of aspirin, an anti-
`lntended Patient Population
`platelet agent, and omeprazole, a proton pump
`inhibitor, indicated for patients who require aspirin for
`secondary prevention of cardiovascular and
`cerebrovascular events and who are at risk of
`
`Maximum Daily Dose
`
`develo 0 in ; asin'n associated astric ulcers.
`1 tablet daily
`’
`
`omeprazole: immediate release)
`
`Route of Administration
`
`Oral
`
`(delayed release tablets (aspirin: delayed release;
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 4 of 53
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`Executive Summary
`
`1.
`
`Recommendations and Conclusion on Approvability
`
`This applicant has provided sufficient CMC information to assure the identity, strength,
`purity, and quality of the drug product before the drug administration.
`
`The Office of Facility and Process has made a final overall “Approve” recommendation
`for the manufacturing inspection of facilities involved in this application.
`
`Labeling and labels are deemed satisfactory from the CMC perspective.
`
`The issue raised by the Biopharmaceutics Review about acid degradation of omeprazole
`in the stomach is deemed to be beyond the Biophannaceutics’ purview and its safety
`concern is deferred to Clinical Team, but OPQ will support and cooperate with any post
`approval investigation on this issue, if it be warranted by the Clinical Team.
`
`Therefore, from the OPQ perspective, this application is recommended for Approval with
`expiration dating period of 36 months.
`
`11.
`
`Summary of Quality Assessments
`
`A. Product Overview
`
`Aspirin and omeprazole are the two active pharmaceutical ingredients of the drug product
`YospralaTM (81 mg or 325 mg aspirin/ 40 mg omeprazole) tablets. The proposed drug
`product is an aspirin delayed-release/omeprazole immediate-release tablet. The listed
`drugs for this 505(b)(2) application are Ecotrin® GSK (aspirin) and Prilosec®
`AstraZeneca (omeprazole), both are delayed-release.
`
`Aspirin is provided
`
`T
`
`‘ ” Vikki—W " ”‘Lrtfiiiii. ' “W”
`Aspirin. ( 'NI'
`...........-,...................,.....,....-‘:.-;!s.'s.'!.<{!11!sttL—‘.e115.:£5151...
`Slruclurc
`HO
`0
`
`M W t g. moi)
`Molecular Formula
`(‘AS RN
`
`(Golf...
`
`.3”, 1(-
`("nuxol
`50-78-2
`
`"M"
`
`(5M4)
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 5 of 53
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`Omeprazole’s chemical structure is shown below:
`(A)
`
`ml
`
`\DflNHH ;
`
`E
`
`;:;—Smn3
`
`l-::'H-:mjfc“
`
`MH‘W
`
`The stability of omeprazole1n solutionis a fimction ofpH, it is rapidly degraded in acid
`media, but has acceptable stability under alkaline conditions. Omeprazole is a racemate
`of two enantiomers, as shown in the figure above.
`
`nedmspmductmanuracmngstepsuse—
`The tablets for both strengths consist of an aspirin core
`
`that is coated with
`
`film coats,
`
`as shown below:
`
`
`
`For detailed composition of. film coats, please see the Drug Product section of this
`review.
`
`B. Quality Assessment Overview
`
`The drug substance reviewer, Dr. Xavier Ysem, concludes that the quality of “the
`described drug substances is deemed acceptable to support their use in the manufacture of
`the proposed drug product YospralaTM (81 mg or 325 mg aspirin/ 40 mg omeprazole)
`tablets as described under Applicant’s NDA 205-103”.
`
`As per Drug Product reviewer, the aspirin mixture supplied is supported by stability results for the drug product.
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 6 of 53
`
`Effective Date: 18 Feb 2016
`
`

`

`
`
`No significant differences have been observed for the real time stability results
`comparing the'drug products using I aspirin and drug products using- aspirin
`(see review #2 in the previous review cycle). Therefore, the proposed 36 months
`expiration dating period is granted for the drug product stored at USP room temperature
`condition based on the 36 months long term stability data for the drug products
`manufactured with aspirin— Post-approval stability protocol and'
`commitment are adequate.
`
`The Process Review states that there are no changes—
`— in the manufactufing and commercial
`packaging configurations for PA8140 tablets and PA32540, and the proposed change of
`batch sizes for the commercial production is deemed acceptable. The firm provided
`adequate information for in-process controls and for the commercial scale-up.
`
`Regarding the Microbiology assessment, the review of the original submission dated 08-
`Jul-2013 remains adequate for microbial limit specifications for the drug product, as there
`are no changes in the control of microbial limits in the current resubmission
`
`Biopharmaceutics Review dated 9-Aug-2016 made a recommendation of approval, but
`raised a concern regarding the degradation of omeprazole in the acidic medium of
`stomach: As stated in the review,
`
`“The dissolution ofYosprala tablet in acid medium (0.1 N HCl) demonstrated that
`
` ”, see graph below:
`
`
`
`However, in the addendum dated 17-Aug-2016 to the the previous Review (9-Aug-2016),
`Biopharmaceutics Team states that safety concern in-vivo about these degradants is
`beyond the Biopharmaceutics purview and is deferred to pre-clinical and clinical teams.
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 7-of 53
`
`Efl'ective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`The Oflice of Facility and Process has made a final overall manufacturing Inspection
`“Approve” recommendation for the facilities involved in this application, as illustrated in
`the inspectional assessment report below:
`
`Moodmmm sue-u
`nun-Jinn
`IMMalnvh Minute-r
`
`w"
`
`M
`
`”or”mmW
`lav-n.-
`WM.
`luv—nah
`WAT-u
`w“
`"Iv“
`
`a...“
`
`‘1' um—zosnu-om-im “Mmum
`
`iflmmmm
`W Emmy—fl- mandolin-win“
`
`Yaw Tam mm mt mm: W uferde www- -
`
`mam
`
`' Appmvn Dan's-w -
`“HI-‘0“-
`
`thud
`
`CL Special Product Quality Labeling Recommendations (NDA only)
`
`NA
`
`D. Final Risk Assessment see Attachment
`
`From Initial Risk Identification .
`
`Imam: 318k
`g
`
`Risk
`
`Mitigation
`A- -roach
`
`.
`
`g:1:11:22];
`
`Lifecycle
`
`Considerations] ;
`Comments“
`
`“23’2”,
`
`Factors that
`
`can impact the
`CQA
`
`.
`
`.
`
`.
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 8 of 53
`
`Effective Date: 18 Feb 2016
`
`

`

`Assay, stability
`
`Microbial
`: Limits
`
`0 Formulation
`0 Container closure
`0 Raw materials
`° Process
`
`parameters
`' Scale/equipment
`0 Site
`
`- Formulation
`- Raw materials
`
`0 Process
`parameters
`- Scale/equipment
`- Site
`
`' Formulation
`0 Raw materials
`0 Process
`
`parameters
`° Scale/equipment
`- Site
`
`Degradation of
`unprotected
`omeprazole in
`‘ stomach
`
`PMS are known for
`their chemical
`instability in acidic
`medium.
`
`
`
`QUALITY ASSESSMENT
`
`Suitable
`analytical
`methodology,
`suitable
`
`container closure
`and storage
`conditions
`
`Suitable
`microbial release
`
`testing.
`
`Meeting the
`acceptance
`criterion of the
`
`approved
`dissolution test
`
`Degradation
`studies of
`omeprazole in
`the stomach,
`degradants
`characterization,
`
`Acceptable
`
`Acceptable
`
`Acceptable from
`OPQ perspective,
`but will cooperate
`with 0ND, if
`further clinical or
`preclinical studies
`are warranted.
`
`if it is determined
`that it will pose a
`significant safety
`concern on the
`tients.
`
`Application Technical Lead:
`Moo-Jhong Rhee, PILD.
`Branch V/DNDP II/ONDP
`
`Digitally signed by Moojhmg Rhws
`DN: c=US, o=U.S. Government, ou=HHS, ou=FDA,
`MOOj h 0 n g Rh ee —S ou=PeopIe,cn=Moojhong Rhee -S,
`03234219200300.10011:1300041261
`Date: 2016.08.18 1595:1904'00‘
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 9 of 53
`
`Effective Date: 18 Feb 2016
`
`

`

`
`
`Chemistry Review Data Sheet
`
`NDA 205103
`
`Trade Name
`
`(aspirin and omeprazole) delayed release tablets
`81 mg (or 325 mg)/40 mg
`
`POZEN Inc.
`
`Zhengfang Ge, Ph. D.
`
`Branch IV
`
`Division of New Drug Quality Assessment II
`Office of New Drug Quality Assessment
`
`Division of Gastroenterology and In-Born Error Products
`
`For
`
`Page 1 of 10
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Table of Contents
`
`Table of Contents2
`
`Chemistry Review Data Sheet.............
`
`.........3
`
`The Executive Summary coo.tenet-.0000oicIto-000.0.toanooooooeooooosooooooa.I...0totonoone...canteen-eoanIo-eo7
`
`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 Not-Approval Recommendation........................................................................................ 8
`
`III. Administrative........................................................................................................................... 9
`
`A. Reviewer’s Signature ........................................................................................................................ 9
`
`B. Endorsement Block ........................................................................................................................... 9
`
`C. CC Block.......................................................................................................................................... 9
`
`IV. Attachments ............................................................................................................................. 10
`
`Page 2 of 10
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`. NDA 205103
`
`. REVIEW #2 2
`
`. REVIEW DATE: Doc 9, 2014
`
`. REVIEWER: Zhengfang Ge, Ph.D.
`
`. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`Original
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`
`25-March-2013
`27-March-20 13
`
`30-Aprii-2013
`21 -May-20 1 3
`l3-June-201 3
`
`29-July-2013
`31-July-2013
`8-June-201 3
`
`1 -Aug-20 1 3
`3—Oct-20 1 3
`1 1.Nov-201 3
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissionm Reviewed
`Resubmission
`
`Document Date
`30-June-2014
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Pozen Inc.
`
`Address:
`
`1414 Raleigh Rd, Suite 400
`
`Page 3 of 10
`
`

`

` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Representative: Paul A. Ossi
`
`Telephone:
`
`919-913-1030
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: None
`b) Non-Proprietary Name (USAN): aspirin, omeprazole
`0) Code Name/# (ONDQA only): N/A
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 4
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b)(2)
`
`10. PHARMACOL. CATEGORY: secondary prevention of cardio and cerebro-
`vascular events in patients at risk of developing aspirin-associated gastric ulcers
`
`11. DOSAGE FORM:
`for omeprazole)
`
`Tablets (delayed release for aspirin, immediate release
`
`12. STRENGTH/POTENCY: aspirin/omeprazole 81 mg (or 325 mg)/40 mg per tablet
`
`13. ROUTE OF ADMINISTRATION: oral
`
`14. Rx/OTC DISPENSED:
`
`_X_Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LJNE TRACKING SYSTEM):
`
`SPOTS product — Form Completed
`
`x Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FOR-
`MULA, MOLECULAR WEIGHT:
`
`Page4 of10
`
`

`

`Chemical name: 2-
`
`Aeetoxybenzoic Acid
`USAN: Aspirin
`CAS: 50-78-2
`
`992mm:
`Chemical name: (RS)-5-
`methoxy-Z-((4-methoxy-3,5-
`dimethylpyridin-Z-yl) methyl-
`sulfinyl)-1Hbenzo[d]imidazole
`USAN: Omeprazole
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DMF# TYPE HOLDER
`
`ITEM REFER'
`ENCED
`
`DATERE-
`STATUS’ VIEW COM-
`PLETED
`
`COMMENTS
`
`Adequate Aug-2013 -
`
`8-July-2013
`
`h 'mm
`
`CAS: 73590-5845 C17H19N3038; 345.4 g/mol
`
`
`I
`
`Inade-
`quate‘
`
`adequate
`for this NDA (see
`review #1.
`
`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
`5 - Authority to reference not granted
`6 —— DMF not available
`
`7 — Other (explain under "Comments")
`
`Page 5 of 10
`
`

`

`
`
`Chemistry Review Data Sheet
`
`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
`
`DESCRIPTION
`APPLICATION NUMBER
`
`
`CON SULTS/ CMC
`RELATED RE-
`VIEWS
`___—
`Withhold
`12/9/2014
`C. C acci-Daniel
`
`Pharm/Tox __—
`Bio harm
`Nov 25, 2014
`B. Zolnik, PhD
`
`
`___—
`
`
`Methods Validation ___
`DMEPA __—
`
`EA
`Categorical Exclusion is
`Zhengfang Ge, Ph.D.
`claimed and is , anted.
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`
`
`
`
`
`
`
`
`
`
`
`18. STATUS:
`
`ONDIA:
`
`
`
`
`
`
`
`Microbiology
`
`Approval
`
`July 8, 2013
`
`Jessica G. Cole, PhD
`
`Page6 oflO
`
`

`

`
`
`Chemistry Assessment Section
`
`The Chemistry Review for NDA 205103
`
`The Executive Summafl
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The CMC Review #1 dated 24-April-2014 had noted the following pending issue:
`
`21CFR 314.125(b)(l3)
`.
`the Office of Compliance issued an overall “Withhold” recommendation for
`the inspections of the manufacturing facilities.
`
`And the Office of Compliance issued another overall “Withhold” recommendation for
`the facilities in this resubmission (see the Attachment), therefore, from the ONDQA
`perspective, this NDA is not recommended for approval in its present form per 21CFR
`314.125(b)(l3).
`
`B. 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)
`
`Drug Substancejs!
`
`Aspirin, USP is supplied
`
`(m4)
`
`Omeprazole is manufactured
`See CMC Review #1 for other information.
`
`(IMO
`
`Drug Products
`
`PA32540 Tablets (325 mg aspirin/40 mg omeprazole) and PA8140 Tablets (81 mg aspirin/40 mg
`omeprazole) are oval, blue-green, film coated tablets with “325/40” or “81/40” printed in black
`on one side. The products are packaged with 830, 90
`MW count configuration in white high
`density polyethylene (HDPE) bottle with a
`“"9 screw cap closure
`”‘4’
`
`Page 7 of10
`
`

`

`
`
`Chemistry Assessment Section
`
`(5)“) All excipients are compendial
`which were previously found acceptable.
`
`The drug products will be manufactured
`
`0"“)
`
`(law
`
`For the tablets of 325 mg aspirin and 40 mg omeprazole (PA32540), stability data obtained at the
`long term condition (25°C/60%RH) over 36 months and at accelerated condition over 6 months
`met the specification for the tablets stored in $230, 90
`(5)“) count HDPE bottles. No signifi-
`cant trends in stability data were observed for appearance, aspirin assay, omeprazole assay, aspi-
`rin dissolution and omeprazole dissolutions. The proposed expiration dating period of 36 months
`is acceptable based on the real time stability data.
`
`For the tablets of 81 mg aspirin and 40 mg omeprazole (PA8140), stability data obtained at the
`long term condition (25°C/60%RH) over 12 months, and 6 months at the accelerated conditions
`(40°C/75%RH) for 6 months met specifications for all bottle packaging configuration:
`(”"9"
`(m4)
`
`(see the Review #1 dated 11/2 1/ 13 for more detailed information)
`
`B. Description of How the Drug Product is Intended to be Used
`
`See CMC Review #1
`
`C. Basis for Not-Approval Recommendation
`
`21 CFR 314.125 (b)(13)
`-
`The Office of Compliance has issued an overall “Withhold” recommendation for the
`facilities involved in this resubmission (see the Attachment).
`
`Page 8 of 10
`
`

`

`
`
`Chemistry Assessment Section
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`Zhengfang Ge, PhD.
`Reviewer/ONDQA
`
`Z he n gfa n g Ge smmmm
`ou-FDA. ou-Penple. cn-zhengtang Ge -A,
`'
`Dale: zomzm 10:5er 05'00'
`A
`<_
`. oszuzwzoozanJmIJ-uoousssu
`
`Digltally signed by Moojhong Rhee —5
`ON: c=US, o=U.S. Govemment, ou=HHS,
`—S ou=FDA, ou=People. cn=Moojhong Rhee -S,
`v
`0.92342.19200300.100.1.1=1300041261
`Date: 2014.1239 1 |:041)9 05‘00'
`
`Moo-Jhong Rhee, PhD.
`Branch Chief/ONDQA
`
`Moojhong Rhee
`
`B. Endorsement Block
`
`Zhengfang Ge, Ph.D.
`Reviewer/ONDQA
`
`Moo-Jhong Rhee, Ph.D.
`Branch Chief/ONDQA
`
`Marie Kowblansky, Ph.D. CMC Lead/ONDQA
`
`C. CC Block
`
`Page 9 of 10
`
`

`

`
`
`Chemistry Assessment Section
`
`IV. Attachments
`
`m,‘
`My ‘~.
`
`Overall Manufacturing Inspection Recommendation
`NDA 205103-0dol—Resuhmbsion/Class 2(36)
`
`Facliltv mummies: — Overall migylimthm Remmnmmlatinn
`
`Facility Inspection - Overall Application Recmmendation
`Withhold
`
`Facility Inspettion - Overall Application Re—evaluation Date
`3/3] 15
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`Page 10 of10
`
`

`

`
`
`
`NDA 205103 Biopharmaceutics Review
`
`
`
`BIOPHARMACEUTICS REVIEW
`
`
`
`
`
`
`
`
`
`
`
`Office of New_DrugQuality Assessment
`T1NDA 205103 (Re—submission)
`Reviewer'
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`~
`,
`,
`,, 7 ,1, Banu SizanliZolnik, Ph.D.
`Division of Gastroenterology and
`
`
`
`
`Inborn Errors Products
`
`
`
`Pozen
`T
`
`7
`
`
`
`7
`
`7
`
`,,,‘_,
`
`
`
`Actin Team Leader:
`
`
`
`
`
`
`
`E15_beth_Chi1<hale Ph. D.
`_.,
`, ,_s T_TT
`
`
`T 4:111:13“
`
`
`
`
`
`
`Generic Name,
`.Asplrin/Omeprazole 81/40 mg,
`T
`
`
`
`
`
`
`
`
`
`
`Secondary prevention of cardio-
`
`
`
`and cerebrovascular events in
`
`
`
`
`
`
`
`
`
`patients at risk of developing
`
`
`
`
`as irin associated _astric ulcers‘J
`Modified Relase Tables(bilayer
`
`
`
`
`- IR/DR)
`Route ofAdministration. Oral
`
`
`
`
`
`
`T» Key review
`
`'
`
`
`
`
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`
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`
`
`
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`
`
`
`
`
`
`1_11
`
`
`
`
`
`
`
`
`SUBMISSIONS REVIEWEDIN THIS DOCUMENT
`Submission Dates
`
`
`
`
`
`
`
`June 30, 2014 (Resubmission)
`
`
`
`
`
`T
`
`TTl
`
`
`
`
`
`
`
`
`T Tp
`
`'
`7 WT 1
`e of
`
`
`
`
`
`
`T Submission:
`T 505 b) 2)A llcat1on
`
`
`
`
`
`
`
`
`
`
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`T 22/12
`W
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`Page 1 of 2
`
`
`
`

`

`NDA 205103 Biopharmaceutics Review
`
`EXECUTIVE SUMMARY
`
`This is a resubmission of NDA 205103 which was issued a Complete Response (CR) action due
`to facility inspection related deficiencies.
`
`In the Original Application, the Applicant, Pozen, submitted a 505(b)(2) NDA for
`Aspirin/Omeprazole 81/40 mg and Aspirin/Omeprazole 325/40 mg Tablets , indicated for use in
`the secondary prevention of cardio— and cerebrovascular events in patients at risk of developing
`aspirin associated gastric ulcers. Both strength tablets consist of an aspirin pH sensitive delayed
`release core
`‘5’“) and an omeprazole coat with immediate
`release characteristics.
`
`During the first cycle of the Biopharmaceutics Review, the dissolution method was found
`acceptable, however, the dissolution acceptance criteria for both strengths were found acceptable
`in an interim basis.
`(”“9
`
`RECOMMENDATION
`
`From the biopharmaceutics perspective, the original NDA was recommended for approval. In this
`submission, there are no new biopharmaceutics study/data included for review. Therefore, this
`Application is acceptable fiom the biopharmaceutics perspective; however note that there are
`two PMCs to be fulfilled.
`
`Banu Sizanli Zolnik, Ph. D.
`Biopharmaceutics Reviewer
`Office of New Dru
`uali Assessment
`
`Elsbeth Chikhale, Ph.D.
`Biopharmaceutics Team Leader (Acting)
`Office of New Dru
`uali Assessment
`g
`
`wavmmwunus
`”it“
`Banu S Zinniifiétm’
`O'HBUWSZUM 5.
`Z i
`. k _
`0.91341 19mm.im.i.r=m
`o n I
`3.13331“le um 39
`"W
`
`E15 beth G.
`
`Digitally slgned by Elsbeth 6.
`
`DN: c=US, o=U.S. Government,
`ou=HHS, ou=FDA, ou=People,
`o
`C h I kh a Ie — 0.9.2342.19200300.100.l.1=130
`0136142, cn=Elsbeth G.
`Chikhale -S
`Date: 2014.1 1.25 10:33:25
`45'00'
`
`5
`
`Page 2 of 2
`
`

`

`Memorandum
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Date:
`
`April 24, 2014
`
`From:
`
`Zhengfang Ge, Ph.D.
`CMC Reviewer, Branch IV
`
`Division of New Drug Quality Assessment II
`ONDQA
`
`Through:
`
`Moo-Jhong Rhee, Ph.D.
`Chief, Branch IV
`
`Division of New Drug Quality Assessment II
`ONDQA
`
`To:
`
`CMC Review #1 of NDA 205103
`
`Subject:
`
`Final Recommendation
`
`The CMC Review #1 dated 21-Nov—2013 had noted the following two pending issues:
`
`1. 21CFR 314.125(b)(l3)
`
`0
`
`Inspection of the manufacturing is pending overall recommendation from the
`Office of Compliance on the site acceptability.
`
`2.
`
`21 CFR 314.125(b)(1)
`
`0 Drug product specification is not adequate pending resolution on dissolution
`test
`
`And because of these deficiencies, in the CMC Review #1, this NDA was not
`
`recommended for approval from the ONDQA perspective.
`
`On March 17, 2014, the Biopharm reviewer Dr. B. Zolnik concluded that the dissolution
`testing is acceptable on an interim basis for the current acceptance criteria for PA8140 and
`PA3 2540 Tablets and recommended Approval for the NDA. The drug product specification
`is now acceptable. (see Attachment 1, Drug Product Specification)
`
`On April 24th, 2014, the Office of Compliance issued an overall “Withhold”
`recommendation for the inspections of the manufacturing facilities (see Attachment 2,
`BER Report).
`
`In addition, the applicant submitted an amendment on Jan. 23, 2014. The amendment
`provided investigation
`00(4)
`
`Reference ID: 3495508
`
`

`

`
`
`
`In file Executive Summary of the
`Substance in Review #1, there is a
`for
`om
`1e. 0n
`e 8 Inoted that
`
`& Them
`mums w o
`rep c
`
`
`with “omeprazole”.
`
`Final Recommendation:
`
`From the 0NDQA perspective, this NDA is recommended for Complete Response per
`21CFR 314.125(b)(l3).
`
`Reference ID: 3495508
`
`

`

`Attachment 1: Drug Product Specification
`
`1. Specification for PA 8140 Tablets
`
`Table 1:
`
`Quality Control Specifications
`
`Blue-Green, film-coated, oval tablet,
`printed with “81/40" in black on one
`stde
`
`p14100 _ Visual inspection
`
`Identification {m Aspilill by HPLC/UV Positive - The retention time for the
`aspirin peak is within 34. ofthe
`standard peak
`"
`
`Identification forAspirinbyFT—IR'
`
`Assay for Aspirin by HPLC/UV
`
`'
`
`Uniformity ofDosage Units for Aspirin Meets the requirements of the
`by HPLC
`
`Related Substances for Aspirin by
`HPLC/UV
`
`'
`
`'
`
`929905 _ Rpm/UV
`
`881700—FT-IR
`
`929905 - HPLC/Uv
`
`929905 _ Hch/[Jv
`
`929905 — HPm/UV
`
`Identification fin Omeprazole by
`l-lPLC/UV
`
`Positive - The retention time for the
`omeprazolepakiswithin 37. of
`
`929906 — flPLC/UV
`
`
`
`Identification for Onteptazole by TLC '
`
`Assay for Omeprazole by HPLC/UV
`
`Uniformity of Dosage Units for
`Omeprazole by HPLC/UV
`
`Related Substances for Omeprazole by
`HPLC/UV
`
`'
`
`'
`
`Dissolution - Acid Resistance for
`Aspirin (0.1 N HCl)
`
`'
`
`.
`
`Dissolution for Aspirin (pl-I 6.8)
`
`Meets theWIS of the
`current35? on
`=
`«6 at
`(Q
`‘0
`w
`
`' ates
`)
`
`Dissolution f0! Omeptazole
`(pH 7.4)
`
`Meets the [alums of fin
`current USP
`(Q = 3% at 8mm)
`
`881600 - TLC
`
`929906 _ I-IPIII/UV
`
`929906 _ l-IPILTIUV
`
`i
`
`‘
`
`929909 _ l-IPIIIIUV
`
`929907 — HPLC/UV
`USP dissolution Apparatus l
`(basket) at 100 rpm
`120 minutes in 900 ml. 0.1M
`h drochloric acid at 310°C
`
`929907 — HPLC/UV
`3:??me Apparatus 1
`C‘ at 100 rpm
`120 minutesin900mL0.lM
`hydrochloric acid at 310°C
`followed by media replacement
`with 900 mL phosphate bufi'er
`~ H 6.8 at 310°C
`
`929908 - HPLCIUV
`USP dissolution Apparatus 1
`(basket) at 100 rpm
`Media - 900 mL phosphate
`bufi'el’ .H 7.4 at 370°C
`
`' Secondary test. Not tested routinely.
`
`Reference ID: 3495508
`
`

`

`2. Specification for PA32540 Tablets
`
`Table 1:
`
`Quality Control Specifications
`
`lMetIIod
`
`P14100 — Visual
`
`Identification for Omeptazole by
`HPLC/UV
`
`'
`
`‘
`
`'
`
`'
`
`'
`
`‘
`
`'
`
`H
`
`’5
`
`881700 — I-T-IR
`
`846520 — HPILI/UV
`
`.
`
`845520 _ HPLC/UV
`
`846630 _ HPLC/UV
`
`881500 'TLC
`846630—HPLCIUV
`
`846630 _ HPMZIUV
`
`i
`
`i
`
`846720 _ HPLC/UV
`
`Identifiation for Aspirin by Fr-m '
`
`Related Substances fm Aspirin by
`HPLC/UV
`
`IdentificationforOmeptazolebyTlfl'
`AssaymemeptazolebyHPLC/UV
`
`Unifotmity of Dosage Units for
`Omepnzole by HPLC/UV
`Related Substances for Omeptazole by
`HPLC/UV
`
`Dissolution - Acid Resistance for
`Aspiiin (0.1 N HCl)
`
`
`
`Meets the tequitenrnts ofthe USP
`
`entrent USP fl
`(Q= 34a: (ominous)
`
`883400 - HPLC/UV
`USP dissolution Appaiatus l
`(basket) at [Mm
`120 minutes in 900mL 0.1M
`- drochloiic acid at 310°C
`
`USP dissolution Appmtus l
`61%!)lequ
`120 minutes in 900 mL 0.1M
`
`hydrochloric acid at 310°C
`followed by media replacement
`with 900 mL phosphate bufi'ei'
`-H 6.8 at 310°C
`
`846330 - HPLC/UV
`USP dissolution Appantus l
`(basket)at1001pm
`_ -900mLp
`bufier H7.4at37.0°C
`
`Dissolution f“Wk
`(PH 7-4)
`
`Mees the requirements of the
`cuttent USP
`= fly.
`0)
`‘
`(Q (Q at (connotes)
`
`' Secondary test. Not tested routinely.
`
`Reference ID: 3495508
`
`

`

`Attachment 2: EER Report
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Appllcauon:
`Ora. Code:
`PliuIin:
`Stamp Date:
`PDUFA one:
`Anion Goal:
`District Goal:
`
`NDA 2051031000
`130
`4
`m—zms
`25-APR—2014
`
`26-Nov-2013
`
`FDA Common:
`
`2‘ GE
`
`c TRAN-ZWAMETZ
`3. BARLEY
`II. KOWBLANSKY
`
`OVOflI Racommondmion:
`
`Sponsor:
`
`POEM INC
`1414 RALEIGH RD STEAM
`CHAPEL HILL, NC 275178834
`YOSPRALA
`
`Brand Name:
`Emu. Name:
`Generic Name:
`Produfl Number: bongo POM: Inamlimt: Show-mils
`001; TIBET; OMEPRAZOLE; 40MG
`001: TMLET: ASPIRIN; 81MB
`00?, TABLET; OMEPRAZOLE; MING
`002 TABIIT; ASPIRIN; 325MG
`
`3017961356
`
`3017953377
`3017902137
`”17%1390
`
`3017963532
`
`Prod QM Rem
`
`Product Oualty PM
`Regulaioly Propel Mgr
`Team L92“!
`
`(HFD-auo)
`
`WITHHOLD
`PENDING
`PENDING
`
`by C. CAPACCLDANIEL
`on 24—APR-2014
`on own-2013 by EES_PROD
`on ozmv—mn m EES_PROD
`
`(}
`
`Establishment:
`
`CFN:
`
`FEI:
`
`0’)“,
`
`0) (9
`
`ONE No:
`Rosponsibiitios:
`
`”'0'“?
`Last Milestone:
`Ililestone Date:
`Declslon:
`Reason:
`
`onus SUBSTANCE LABELER
`DRUG SUBSTANCE MAWFACTURER
`DRUG NBSTANCE OTl-ER TESTER
`DRUG SJBSTANCE PACKAGE?
`
`oc RECOMMENDATION
`24-APR-ZO14
`wmmou)
`DISTRICT RECOMMENDATION
`
`AADA:
`
`”(4)
`
`(MI sums:
`
`NONE
`
`Reference ID: 3495508
`
`

`

`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SU MMARY REPORT
`
`Establishment:
`
`CFN: - FEI: _
`
`DMF No:
`
`Responsmmes:
`
`Profile:
`
`Last Milestone;
`“lestone Date:
`
`Decision:
`Reason:
`
`AADA:
`
`DRUG SUBSTANCE OTHER TESTER
`FNISHED DOSAGE MANUFACTURER
`FNISHED DOSAGE OTHER TESTER
`FINISHED DOSAGE PACKAGER
`FMISHED DOSAGE STABILITY TESTER
`
`TABLETS, PROM’T RELEASE
`
`OAI Status:
`
`NONE
`
`oc RECOMMENDATION
`22-JUL-2013
`
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`
`Establshment:
`
`CFN: - DMF No:
`
`Ramon-imitates:
`
`DRUG SUBSTANCE LABELER
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE OTHER TESTER
`DRUG SUBSTANCE PACKAGER
`
`Profile: — OAI Status:
`“3‘ Milestone:
`0C RECOMMENDATION
`Mlestone Date:
`HUM-2014
`
`NONE
`
`Decision:
`
`Reason:
`
`ACCEPTABLE
`
`DIS'IRicT RECOMMENDATION
`
`Reference ID: 3495508
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ZHENGFANG GE
`04/24/2014
`
`MOO JHONG RHEE
`04/24/2014
`Chief, Branch IV
`
`Reference ID: 3495508
`
`

`

`NDA 205-103 Biopharmaceutics Review
`
`
`
`
`Application No.:
`
`
`Division:
`
`Applicant:
`
`Trade Name:
`Generic Name,
`Strength:
`
`Indication:
`
`Formulation:
`
`
`BIOPHARMACEUTICS REVIEW
`Office of New Drug Quality Assessment
`
`NDA 205-103
`
`Division of
`Gastroenterology and
`Inborn Errors Products
`Pozen
`Yosprala
`PA8140 and PA32540
`Aspirin/Omeprazole, 81/40
`mg, 325/40 mg Tablets
`Secondary prevention of
`cardio- and
`cerebrovascular events in
`patients at risk of
`developing aspirin
`associated gastric ulcers
`Modified Release Tables
`(bilayer IR/DR)
`
`Reviewer:
`Banu Sizanli Zolnik, Ph.D.
`
`Secondary Signature:
`Sandra Suarez Sharp, Ph.D.
`Acting Supervisor:
`Richard Lostritto, Ph.D.
`Date Assigned: April 2, 2013
`
`Date of Review: March 17, 2013
`
`Route of Administration: Oral
`
`SUBMISSIONS REVIEWED IN THIS DOCUMENT
`Date of
`PDUFA
`informal/
`DATE
`Formal Consult
`
`Submission Dates
`March 25, 2013 Original Application
`June 13, 2013 Seq. # 0005
`July 31, 2013 Seq. # 0012
`August 1, 2013 Seq. #0013
`September 4, 2013 Seq. #0014
`October 4, 2013 Seq. #0015
`November 14, 2013 Seq. #0020
`January 8, 2014 Seq. #0026
`March 21, 2014 Seq.#0031
`Type of Submission:
`
`NA
`
`April 25, 2014
`
`
`505 (b) (2) Application
`
`1. Dissolution method and acceptance criteria
`2. In vitro alcohol dose dumping studies
`3. The data supporting appropriate bridging across the phases
`of formulations to the To-be-Marketed Formulation
`
`
`Page 1 of 32
`
`
`Key review points
`
`
`
`
`
`
`
`
`Reference ID: 3475484
`
`

`

`NDA 205-103 Biopharmaceutics Review
`
`TABLE OF CONTENTS
`
`I) SUMMARY OF BIOPHARMACEUTICS FINDINGS .............................................. 4
`1
`II) RECOMMENDATION ....................................................................................................... 7
`III) QUESTION BASED REVIEW – BIOPHARMACEUTICS EVALUATION .................. 8
`A) GENERAL ATTRIBUTES .............................................................................................. 8
`1 What are the highlights of the chemistry and physico-chemical properties of the drug
`substance (e.g. solubility) and formulation of the drug product? .............................................. 8
`Is there any information on BCS classification? What claim did the applicant make based
`2
`on BCS classification? What data are available to support this claim? .................................. 10
`B) DISSOLUTION INFORMATION .................................................................................... 10
`B.1. DISSOLUTION METHOD ............................................................................................. 10
`3 What is the proposed dissolution method? ..................................................................... 10
`4 What data are provided to support the adequacy of the proposed dissolution method (e.g.
`medium, apparatus selection, etc.)? ........................................................................................ 11
`5 What information is available to support the robustness (e.g. linearity, accuracy, etc.) of
`the dissolution methodology? ................................................................................................. 13
`6 What data are available to support the discriminating power of the method? ................ 13
`Is the proposed dissolution method bio-relevant? What data are available to support this
`7
`claim? ...................................................................................................................................... 19
`8
`Is the proposed method acceptable? If not, what are the deficiencies? .......................... 19
`The Applicant provided adequate information to support the acceptability and discriminating
`power of the proposed dissolution method (e.g., the method is sensitive to cha