`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203794Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`MEMORANDUM: DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC
`HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`DATE:
`
`TO:
`
`FROM:
`
`
`
`19-SEP-2012
`
`N203794 File
`
`Craig M. Bertha, Ph.D.
`Chemistry Reviewer
`ONDQA, Division III, Branch VIII
`
`
`THROUGH: Prasad Peri, Ph.D.
`
`
`Branch Chief
`
`
`ONDQA, Division III, Branch VIII
`
`SUBJECT: ACCEPTABLE recommendation from the Office of Compliance for application
`of 18-SEP-2012; Final CMC recommendation
`
`
`SUMMARY: The Office of Compliance has placed an overall recommendation of
`ACCEPTABLE into the EES on 18-SEP-2012. The CMC team can now recommend that the
`application be approved.
`
`RECOMMENDATION: The application is recommended for approval.
`
`
`
`
`
`
`
`
`cc:
`OND/DAAAP/DChiapperino
`ONDQA/DIV 1/CBertha/19-SEP-2012
`ONDQA/DIV 1/PPeri_______________
`ONDQA/DIV1/DChristodoulou
`OND/DAAAP/EFields
`ONDQA/LRivera
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_______________________________
`Craig M. Bertha, Ph.D.
`Chemist
`
`Reference ID: 3191151
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CRAIG M BERTHA
`09/19/2012
`
`PRASAD PERI
`09/20/2012
`I concur
`
`Reference ID: 3191151
`
`

`

`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 203794
`
`
`Nucynta® (tapentadol) Oral Solution
`
`
`Janssen Pharmaceuticals, Inc.
`
`
`
`Craig M. Bertha, Ph.D.
`Office of New Drug Quality Assessment
`Division III/Branch VIII
`
`for
`
`Division of Anesthesia, Analgesia, and Addiction Products
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3174017
`
`
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`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. Endorsement Block........................................................................................................................... 8
`
`C. CC Block.......................................................................................................................................... 8
`
`Chemistry Assessment .............................................................................................9
`
`Reference ID: 3174017
`
`Page 2
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 203794
`
`2. REVIEW #: 3
`
`3. REVIEW DATE: 13—AUG—20 1 2
`
`4. REVIEWER: Craig M. Bertha, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`Original
`Amendment
`
`15-DEC-201 1
`03—APR—2012 (response to CMC DR)
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 5! Reviewed
`
`Amendment
`
`Amendment (reviewed by microbiology team)
`Amendment (reviewed by microbiology team)
`Amendment
`Amendment
`Amendment
`
`Document Date
`
`07-MAY—20 12
`
`07-MAY—2012
`l3-IUN—2012
`l8-JUN-2012
`03-AUG-2012
`10-AUG-2012
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Ortho-McNeil—Janssen Pharmaceuticals, Inc.
`
`Reference ID: 3174017
`
`Page 3
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Janssen Research & Development, L.L.C.
`920 Route 202 PO. Box 300
`
`Raritan, NJ 08869
`
`Address; On behalfof
`Janssen Pharmaceuticals, Inc.
`1125 Trenton-Harbourton Road. PO. Box 200
`Titusville. NJ 08560-0200
`
`Representative:
`
`Peggy Ferrone, Manager, Regulatory Affairs
`
`Telephone:
`
`908-704-5 1 l6
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Nucynta®
`b) Non-Proprietary Name (USAN): tapentadol
`c) Code Name/# (ONDQA only): R331333, CG5503, BN200, CAS No. 175591-09—0
`d) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`tapentadol is a centrally acting
`10. PHARMACOL. CATEGORY:
`analgesic proposed for the relief of moderate to severe acute pain in patients
`18 years of age or older; analgesia is thought to be due to mu-opioid activity
`and inhibition of norepinephrine uptake
`
`11. DOSAGE FORM:
`
`oral solution
`
`12. STRENGTH/POTENCY: 20 mg tapentadol (23.3 tapentadol
`HCl) per mL of solution
`
`13. ROUTE OF ADMINISTRATION: oral
`
`l4. Rx/OTC DISPENSED: LRX
`
`_OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LlNE TRACKING SYSTEM 1:
`
`Reference ID: 3174017
`
`Page 4
`
`

`

`‘..x.“
`
`m ‘
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`.‘.x.“
`
`t m: ‘
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`
`
`Chemical Name:
`monohydrochloride
`Molecular formula:
`
`3-[(lR,2R)-3-(dimethylamino)—l-ethyl-2-methylpropyl]phenol
`
`CHHBNO-HCI
`
`Molecular Weight:
`CAS:
`
`257.81 g/mol; Free base: 221.35 g/mol
`175591-09-0
`
`l7. RELATED/SUPPORTING DOCUMENTS:
`
`A. Supporting DNIFs:
`
`ST TUSZ
`
`DATE REVIEW
`COWLETED
`lS-APR-2012
`
`—N
`
`oplodllctconhctsee
`P.7enluafiul
`
`I I
`
`l7-JAN-2012
`
`07-AUG-2012
`
`--_ i - -
`
`Reference ID: 3174017
`
`Page 5
`
`

`

`
`
`Chemistry Review Data Sheet
`
`lAction 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)
`3 Include reference to location in most recent CMC review
`
`B. Other Supporting Documents:
`
`
`
`C. Related Documents:
`
`APPLICATION
`
`200533
`
`Janssen Pharmaceuticals. Inc. A roved 25-AUG-2011: ER tablet
`
`Pharmaceutical R&D. LLC
`
`Pharmaceutical R&D. LLC
`
`Pharmaceutical R&D. LLC
`
`
`
`17—, 23-JAN-2012 &
`06—FEB—2012
`
`— IA
`Pending
`
`COMMENTS
`
`Microbiology
`
`Microbial limits testing,
`preservative absence
`
`12—JAN-2012
`
`— N/A
`— N/A
`— N/A
`— N/A
`— N/A
`Final/B. Riley PlLD.
`Recommend appmval on the basis of
`product quality microbiology
`
`Reference ID: 3174017
`
`Page 6
`
`

`

`
`
`The Chemistry Review for NBA 203794
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is considered to be approvable as the recommendation from the
`Office of Compliance is pending.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`
`and/or Risk Management Steps, if Approvable
`
`None at this time.
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug product is Nucynta® (tapentadol) Oral Solution and it is indicated for
`the relief of moderate to severe acute pain in patients 18 years of age or older.
`The drug substance is tapentadol hydrochloride, which is a chiral opioid
`compound obtained by chemical synthesis
`(m4)
`The drug has already been approved for use to
`treat moderate to severe acute and chronic pain with immediate and extended
`release solid oral dosage forms, respectively. The
`(m4) form of the drug
`substance is inconsequential as it is formulated in solution. The drug substance is
`manufactured for Janssen and information regarding the manufacturer of the drug
`substance is held in DMF war
`
`M4). The aqueous-based solution
`The drug product is manufactured by
`formulation contains no co-solvents, has a target pH of 4.0, and also contains both
`sucralose and a proprietary flavor mixture, for taste purposes. The clear and
`colorless formulation is simply prepared by
`. The strength of the formulation, in terms of the tapentadol
`base, is 20 mg/mL (equivalent to 23.3 mg of tapentadol hydrochloride), and the
`formulation is packaged in quantities of 100 and 200 mL in high density
`polyethylene bottles fitted with foil induction seals and
`(mo closures.
`To ensure accurate dosing, the bottled product is packaged with an oral dosing
`syringe
`(no) that includes three gradations corresponding to doses of 50, 75
`and 100 mg of tapentadol. This dosing syringe also comes with a bottle adapter
`which is inserted by the patient into the bottle after removal of the foil induction
`seal. A 24 month expiration dating period is supported by the stability data that
`
`(h) (4)
`
`Reference ID: 3174017
`
`Page 7
`
`

`

`
`
`have been provided in the application and the product is intended to be stored at
`room temperature.
`
`B. Description of How the Drug Product is Intended to be Used
`
`The drug product packages of 100 and 200 mL of formulation have a
`concentration of 20 mg/mL and provide 20—40 and 40-80 doses, respectively,
`corresponding to the labeled doses of 50-100 mg to be taken every 4-6 hours.
`Daily doses of more than 700 mg the first day and more than 600 mg on
`subsequent days are not recommended by the applicant in the label.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The recommendation from the Office of Compliance for the application is
`PENDING. Note that the CMC-related labeling comments captured in the first
`review have not been conveyed to the applicant.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Craig M. Bertha. Ph.D./Chemistry Reviewer: 13-AUG-2012
`
`Prasad Peri. PhD/Branch Chief
`
`C. CC Block
`
`DChristodoulou/DNDQA III
`DChiapperino/DAAAP
`KRiviere/ONDQA
`DBaugh/OSE/OMEPRM/DMEPA
`EFields/DAAAP
`AEmami/DAAAP
`
`LRivera/ONDQA
`YZhou/OB/DBH
`DLee/OCP/DCPII
`
`7 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 3174017
`
`Page 8
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CRAIG M BERTHA
`08/14/2012
`
`PRASAD PERI
`08/14/2012
`I concur
`
`Reference ID: 3174017
`
`

`

`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 203794
`
`
`Nucynta® (tapentadol) Oral Solution
`
`
`Janssen Pharmaceuticals, Inc.
`
`
`
`Craig M. Bertha, Ph.D.
`Office of New Drug Quality Assessment
`Division III/Branch VIII
`
`for
`
`Division of Anesthesia, Analgesia, and Addiction Products
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3121241
`
`
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`1. Recommendations ...................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 7
`
`B. Reconmlendation 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. Endorsement Block........................................................................................................................... 8
`
`C. CC Block.......................................................................................................................................... 8
`
`Chemistry Assessment .............................................................................................9
`
`Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2:
`I.
`Body Of Data ............................................................................................................9
`
`
`Review of 03-APR-2012 Amendment ............................................................................................ 9
`
`Reference ID: 3121241
`
`Page 2
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 203794
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: 24—APR—2012
`
`4. REVIEWER: Craig M. Bertha, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Original
`
`Document Date
`
`lS-DEC-ZOll
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 5! Reviewed
`
`Document Date
`
`Amendment
`
`03—APR—2012 (response to CMC DR)
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`
`Janssen Research & Development. L.L.C.
`920 Route 202 RC. Box 300
`Raritan. NJ 08869
`
`Address: On behalf of
`Janssen Pharmaceuticals, Inc.
`1125 Trenton—Harbounon Road. PO. Box 200
`Titusville. NJ 08560-0200
`
`Representative:
`
`Peggy Fen'one. Manager, Regulatory Affairs
`
`Telephone:
`
`908-704-51 16
`
`Reference ID: 3121241
`
`Page 3
`
`

`

`
`
`Chemistry Review Data Sheet
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`3) Proprietary Name: Nucynta®
`b) Non-Proprietary Name (USAN): tapentadol
`c) Code Name/# (0NDQA only): R331333, CGSSOS, BN200, CAS No. 175591-09-0
`d) Chem. Type/Submission Priority (0NDQA only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`10. PHARMACOL. CATEGORY:
`
`tapentadol is a centrally
`acting analgesic proposed for the relief of
`moderate to severe acute pain in patients 18
`years of age or older; analgesia is thought to
`be due to mu—opioid activity and inhibition
`of norepinephrine uptake
`
`11. DOSAGE FORM:
`
`oral solution
`
`12. STRENGTH/POTENCY: 20 mg tapentadol (23.3 tapentadol
`HCl) per mL of solution
`
`13. ROUTE OF ADMINISTRATION: oral
`
`l4. Rx/OTC DISPENSED:
`
`_)_(‘_RX
`
`OTC
`
`15. SPOTS {SPECIAL PRODUCTS ON-LlNE TRACKING SYSTEM}:
`
`SPOTS product — Form Completed
`
`X
`Not a SPOTS product
`
`Reference ID: 3121241
`
`Page 4
`
`

`

`
`
`Chemistry Review Data Sheet
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`/
`
`'HCI
`
`Chemical Name:
`
`Molecular formula:
`
`3-[(1R,2R)-3-(dimethylamino)— 1-ethyl-2-
`methylpropyl]phenol monohydrochloride
`Cl
`23NO-HCl
`
`Molecular Weight:
`CAS:
`
`257.81 g/mol; Free base: 221.35 g/mol
`175591-09-0
`
`17. RELATED/SUPPORTING DOCUlVIENTS:
`
`A. Supporting DMFs:
`
`HOLDER
`
`ITEM
`REFERENCED
`
`W"
`
`TYPE
`DNIF #
`"M" s
`4
`3
`
`1
`
`2
`
`STATUS
`
`3
`DATE REVIEW
`CODE
`COMNIENTS
`CONIPLETED
`3
`lam-2012 —
`3-_—
`4-
`
`
`
`—N
`
`IA
`
` Ji53his
`N/A -
`
`2
`
`3
`
`Adequate
`
`l7—JAN-2012
`
`1Action 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
`
`Reference ID: 3121241
`
`Page 5
`
`

`

`
`
`Chemistry Review Data Sheet
`
`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)
`3 Include reference to location in most recent CMC review
`
`B. Other Supporting Documents:
`
`ITEM
`mm REFERENCED
`
`COMMENTS
`
`STATUS
`
`DATE REVIEW
`COMPLETED
`
`C. Related Documents:
`
`m—
`
`APPLICATION
`
`Janssen
`Pharmaceuticals, Inc.
`
`Johnson & Johnson
`Pharmaceutical R&D.
`LLC
`
`Johnson & Johnson
`Pharmaceutical R&D,
`LLC
`
`Johnson & Johnson
`Pharmaceutical R&D.
`LLC
`
`Approved 25-AUG-201 1; ER tablet
`
`Active; acute and chronic pain; IR tablet
`
`Active: neuropathic pain: ER tablets
`
`Active: oral solution
`
`
`
`NDA
`
`200533
`
`61345
`
`105766
`
`108134
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`
`STATUS/
`COMNTS
`REVIEWER
`FORWARDED
`CONSULTS
`—————17—, 23——JAN2012&
`06—FEB—2012
`
`PhD.
`
`—————
`m————
`—————
`Methods Validation————
`I_————
`Microbial limits testing,
`lZ-JAN—2012
`1R letter issued 20-APR-2012
`. cscrvative absence
`
`Reference ID: 3121241
`
`Page 6
`
`

`

`
`
`The Chemistry Review for NBA 203794
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is considered to be approvable as there are outstanding CMC-
`related and microbiology issues. Moreover, the facility inspections are
`outstanding and the above CMC recommendation does not incorporate any
`potential facility inspection issues. It is requested that the PM send the
`microbiology inf01mation request to the applicant (see their consult review of 19-
`APR-2012).
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None at this time.
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug product is Nucynta® (tapentadol) Oral Solution and it is to be indicated
`for the relief of moderate to severe acute pain in patients 18 years of age or older.
`The drug substance is tapentadol hydrochloride, which is a chiral opioid
`compound obtained by chemical synthesis
`(on)
`The drug has already been approved for use to
`treat moderate to severe acute and chronic pain with immediate and extended
`release solid oral dosage forms, respectively. The
`(I'm form of the drug
`substance is inconsequential as it is formulated in solution. The aqueous—based
`solution formulation contains no co—solvents, has a target pH of 4.0, and also
`contains both sucralose and a proprietary flavor mixture, for taste purposes. The
`clear and colorless formulation is simply prepared by
`«no
`The strength of the formulation, in terms of the
`tapentadol base, is 20 mg/mL (equivalent to 23.3 mg of tapentadol
`hydrochloride), and the formulation is packaged in quantities of 100 and 200 mL
`in high density polyethylene bottles fitted with foil induction seals and (no)
`closures. To “ensure accurate dosing” the bottled product is packaged
`with an oral dosing syringe that includes three gradations corresponding to doses
`of 50, 75 and 100 mg of tapentadol. A 24 month expiration dating period is
`supported by the stability data that have been provided in the application and the
`product is intended to be stored at room temperature.
`
`Reference ID: 3121241
`
`Page 7
`
`

`

`
`
`B. Description of How the Drug Product is Intended to be Used
`
`The drug product packages of 100 and 200 mL of formulation have a
`concentration of 20 mg/mL and provide 20—40 and 40—80 doses, respectively,
`corresponding to the labeled doses of 50-100 mg to be taken every 4-6 hours.
`Daily doses of more than 700 mg the first day and more than 600 mg on
`subsequent days are not recommended by the applicant in the label.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`There are currently outstanding microbiology issues (IR letter to issue) and the
`recommendation from the Office of Compliance for the application is PENDING.
`There is also a CMC-related issue regarding the dosing pipette accuracy. In
`addition, the CMC-related labeling comments captured in the first review have
`not been conveyed to the applicant.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Craig M. Bertha. Ph.D./Chemistry Reviewer: 24-APR-2012
`
`Prasad Pen'. PhD/Branch Chief
`
`C. CC Block
`
`DChristodoulou/DNDQA I
`DChiapperino/DAAAP
`KRiviere/ONDQA
`DBaugh/OSE/OMEPRM/DMEPA
`EFields/DAAAP
`AEmami/DAAAP
`
`KSharma/ONDQA
`YZhou/OB/DBII
`DLee/0CP/DCP11
`
`10 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 3121241
`
`Page 8
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CRAIG M BERTHA
`04/24/2012
`
`PRASAD PERI
`04/25/2012
`I concur
`
`Reference ID: 3121241
`
`

`

`NDA 203794
`
`MEMORANDUM
`
`
`Date: February 24, 2012
`
`To:
`
`From: Christine M. V. Moore, Ph.D.
`
`Acting Office Director
`
`ONDQA
`
`Subject: ONDQA recommendation on biowaiver for NDA 203794 Nucynta Oral Solution
`
`This memo relates to the suitability of a biowaiver for NDA 203794 Nucynta Oral Solution
`relative to the immediate release tablet. I have reviewed the current and previous review
`documents and related research literature on this matter, and have held meetings with the primary
`reviewer (Dr. Kareen Riviere), the secondary reviewer (Dr. Sandra Suarez-Sharp), and the Acting
`Biopharm Supervisor (Dr. Angelica Dorantes) to discuss the issues related to the suitability of the
`biowaiver. I believe that I have a good understanding of the data available and the regulatory
`requirements. Based on the information reviewed, I deem that the biowaiver granted by ONDQA
`for IND 61,345 on 6/29/09 is valid for NDA 203794.
`
`Background:
`Tapentadol is a highly soluble, highly permeable drug that was granted BCS-1 classification by
`the CDER BCS Committee in September 2008. Immediate release Tapentadol tablets were
`approved by FDA on 11/20/08 for the relief of moderate to severe acute pain in adults. In 2009,
`the applicant requested a biowaiver for an oral solution of tapentadol with two strengths (4 mg/ml
`and 20 mg/ml) relative to the approved immediate tablet. The biowaiver was granted on 6/29/09.
`The 20 mg/ml formulation utilized in NDA 203794 is identical to that previously granted a
`biowaiver in IND 61,345.
`
`Current Issue:
`In the ONDQA Biopharmaceutics Filing Review, the reviewer determined that the previously
`approved biowaiver was not valid for the proposed 20 mg/ml tapentadol oral solution. The
`reviewer states that per the BCS guidance for industry, demonstration in vivo BA or BE data
`may not be necessary for pharmaceutically equivalent drug products containing Class 1 drug
`substances, as long as the active ingredients do not significantly affect absorption of the active
`ingredients. The reviewer believes that the current drug product does not meet this requirement
`because:
`
`
` The proposed product and the reference product do not meet the definition of
`pharmaceutical equivalents in 21 CFR 320.1 because they are not the same dosage form.
`
` 
`
` The proposed product contains sucralose as an inactive ingredient which may affect
`bioavailability.
`
` I
`
` do not find either of these arguments compelling enough to overturn the previous decision to
`grant a biowaiver.
`
`
`Reference ID: 3092576
`
`

`

`Related to the first point, this matter is deemed to be a difference in interpretation of regulations
`and guidance. Neither the regulatory requirements in the CFR nor the related guidance for
`biowaivers have changed since the biowaiver was granted in 2009. While biowaivers for a
`solution with a BCS 1 component is not explicitly discussed in the regulations, it is consistent
`with CDER’s Guidance on Bioavailability and Bioequivalence for Orally Administered Products
`– General Considerations which states “Generally, in vivo BE studies are waived for solutions on
`the assumption that release of the drug substance from the drug product is self evident and that
`the solutions do not contain any excipients that significantly affect drug absorption (21 CFR
`320.22(b)(3)(iii).”
`
`Regarding the second point, I find a negligible risk that the sucralose in the formulation could
`affect bioavailability. While the cited paper (Abou-Donia, et. al 2008) provides information that
`sucralose can affect expression levels of certain enzymes transporters that could affect
`bioavailability of some drugs, it should be noted that this study was performed in animal models
`over an 12 week period of time. The product under consideration is intended for acute pain
`indication and the concentration of sucralose (approximately
` lower than the
`lowest concentration studied in the paper. Furthermore, the cited work has been refuted by later
`authors (
` Finally, the total amount of sucralose in the formulation is quite
`low compared to other food products; a 100 mg tapentadol dose contains
` of sucralose,
`approximately equal to one packet of commercially available sweetener.
`
`Recommendation:
`After reviewing the available information and discussing the issues with Drs. Riviere, Suarez-
`Sharp and Dorantes, insufficient evidence was found to present reverse the biowaiver granted on
`the same formulation on 6/29/09. Consequently, the ONDQA recommendation is that the
`biowaiver be considered valid for NDA 203794. While this decision does not impact the
`ONDQA review of the application, it may affect the Office of Clinical Pharmacology review
`approach.
`
`Reference ID: 3092576
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CHRISTINE M MOORE
`02/24/2012
`
`Reference ID: 3092576
`
`

`

`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 203794
`
`
`Nucynta® (tapentadol) Oral Solution
`
`
`Janssen Pharmaceuticals, Inc.
`
`
`
`Craig M. Bertha, Ph.D.
`Office of New Drug Quality Assessment
`Division III/Branch VIII
`
`for
`
`Division of Anesthesia, Analgesia, and Addiction Products
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3087005
`
`
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
`
`The Executive Summary .........................................................................................8
`
`1. Recommendations ...................................................................................................................... 8
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 8
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or 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.......................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 9
`
`III. Administrative........................................................................................................................... 9
`
`A. Reviewer’s Signature ........................................................................................................................ 9
`
`B. Endorsement Block........................................................................................................................... 9
`
`C. CC Block.......................................................................................................................................... 9
`
`Chemistry Assessment ........................................................................................... 10
`
`Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2:
`I.
`Body Of Data .......................................................................................................... 10
`
`S DRUG SUBSTANCE [tapentadol HCl, Janssen] ...................................................................... 10
`
`P DRUG PRODUCT [tapentadol oral solution] ............................................................................ 11
`
`Pl Description and Composition of the Drug Product [tapentadol oral solution] ............................... 11
`
`P2 Pharmaceutical Development [tapentadol oral solution] ............................................................... 12
`
`P3 Manufacture [tapentadol oral solution] .......................................................................................... 19
`
`R4 Control of Excipients [tapentadol oral solution] ............................................................................ 22
`
`P5 Control of Drug Product [tapentadol oral solution] ....................................................................... 24
`
`R6 Reference Standards or Materials [tapentadol oral solution] ......................................................... 31
`
`P7 Container Closure System [tapentadol oral solution] ..................................................................... 32
`
`Reference ID: 3087005
`
`Page 2
`
`

`

`'"fl‘t
`
`CHEMISTRY REVIEW
`
`f'F'X
`
`P.8 Stability [tapentadol oral solution] ................................................................................................. 37
`
`A APPENDICES ...........................................................................................................................41
`
`Al Facilities and Equipment (biotech only) ........................................................................................ 41
`
`A2 Adventitious Agents Safety Evaluation ......................................................................................... 41
`
`A3 Novel Excipients ........................................................................................................................... 41
`
`R REGIONAL INFORMATION ..................................................................................................41
`
`R1 Executed Batch Records ................................................................................................................. 41
`
`R2 Comparability Protocols ................................................................................................................. 41
`
`R3 Methods Validation Package .......................................................................................................... 41
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ....................................42
`
`A. Labeling & Package Insert ............................................................................................................. 42
`
`B. Environmental Assessment 0r Claim Of Categorical Exclusion .................................................... 43
`
`Reference ID: 3087005
`
`Page 3
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 203794
`
`2. REVIEW #:1
`
`3. REVIEW DATE: 09—FEB—2012
`
`4. REVIEWER: Craig M. Bertha, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`