`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`200533Orig1s000
`
`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:
`
`
`
`25-OCT-2010
`
`N200533 File
`
`Craig M. Bertha, Ph.D.
`Chemistry Reviewer
`ONDQA, Division III, Branch VIII
`
`
`THROUGH: Prasad Peri, Ph.D.
`
`
`Acting Branch Chief
`
`
`ONDQA, Division III, Branch VIII
`
`SUBJECT: Updated dissolution acceptance criteria proposed in the 18-OCT-2010, meeting
`briefing document
`
`
`SUMMARY: The DAAP sent the applicant a complete response letter dated 01-OCT-2010, for
`the application. As a result of an evaluation of the IVIVC models and dissolution data, the
`biopharmaceutics team in ONDQA requested that the applicant revise the dissolution acceptance
`criteria for the drug product. The purpose of this memorandum is to outline the changes
`proposed for the drug product dissolution acceptance criteria and how these relate to the
`dissolution data that have been provided in the application for all strengths of the drug product.
`
`The dissolution specification acceptance criteria that had been proposed in the original
`application and the newly proposed limits, to be applied to all strengths, are outlined in the table
`below.
`
`Dissolution Acceptance Criteria (Original) (% release)
`strength/time
`30 min
`180 min
`50 mg
`100 mg
`150 mg
`200 mg
`250 mg
`Newly proposed limits
`(all strengths)
`
`Based on the 18 months of 25°C/60%RH stability data that have been provided thus far in the
`application for the drug product packaged in both the bottles and blisters, it is likely that the
`dissolution testing will routinely comply with the new acceptance criteria. The following table
`provides the minimum and maximum individual dissolution results that were observed for the
`25°C/60%RH stored drug product in both packaging types.
`
`360 min
`
`600 min
`
`(b) (4)
`
`

`

`N200533
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`p. 2
`
`08G23/100/30
`
`08G25/100/30
`
`08G29/100/30
`
`08G23/100/180
`
`08G25/100/180
`
`08G29/100/180
`
`08G23/100/360
`
`08G25/100/360
`
`08G29/100/360
`
`08G31/150/30
`
`08H04/150/30
`
`08H06150/30
`
`08G31/150/180
`
`08H04/150/180
`
`08H06150/180
`
`08G31/150/360
`
`08H04/150/360
`
`08H06150/360
`
`Minimum and maximum dissolution for bottled and blister packaged drug product on stability over 18 months at 25°C/60%RH
`
`Batch/strength/DissTime
`
`
`
`
`
`
`
`
`08G01/50/30
`08G07/50/30
`08G24/50/30
`08G01/50/180
`08G07/50/180
`08G24/50/180
`08G01/50/360
`08G07/50/360
`08G24/50/360
`Min
`Max
`
`Min
`Max
`
`Min
`Max
`
`Min
`Max
`
`Min
`Max
`
`
`08H20/200/30
`
`08H22/200/30
`
`08H26/200/30
`
`08H20/200/180
`
`08H22/200/180
`
`08H26/200/180
`
`08H20/200/360
`
`08H22/200/360
`
`08H26/200/360
`
`08G09/250/30
`
`08G17/250/30
`
`08G15/250/30
`
`08G09/250/180
`
`08G17/250/180
`
`08G15/250/180
`
`08G09/250/360
`
`08G17/250/360
`
`08G15/250/360
`
`30 min
`
`
`
`
`
`180 min
`
`
`
`
`
`360 min
`
`
`
`
`
`ranges
`
`New
`AC
`
`
`
`
`08G01/50/600
`
`
`
`08G07/50/600
`
`
`
`08G24/50/600
`
`08G23/100/600
`
`08G25/100/600
`
`08G29/100/600
`
`08G31/150/600
`
`08H04/150/600
`
`08H06150/600
`
`08H20/200/600
`
`08H22/200/600
`
`08H26/200/600
`
`08G09/250/600
`
`08G17/250/600
`
`08G15/250/600
`
`600 min
`
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`p. 3
`
`
`
`
`
`N200533
`
`It is also noted that the revised acceptance criteria for the 180 and 360 minute dissolution time-
`points are no longer
` i.e., the limit at which point the ICH Q6A guidance would
`recommend that appropriate bioavailability data be provided to validate the acceptance ranges.
`
`RECOMMENDATION: From a quality control CMC perspective, there is no objection to the
`changes that have been made to the dissolution acceptance criteria. Ultimately, the final
`acceptance of the revised acceptance criteria will be dependent upon the evaluation of the
`biopharmaceutics team.
`
`
`
`
`
`
`
`
`
`
`
`cc:
`OND/DAAP/DChiapperino
`ONDQA/DIV 3/CBertha/25-OCT-2010
`ONDQA/DIV 3/PPeri
`ONDQA/DIV3/DChristodoulou
`ONDQA/SSuarez Sharp
`
`_______________________________
`Craig M. Bertha, Ph.D.
`CMC Reviewer, ONDQA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(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/
`----------------------------------------------------
`
`CRAIG M BERTHA
`10/25/2010
`
`PRASAD PERI
`10/26/2010
`I concur
`
`Reference ID: 2854365
`
`

`

`
`
`MEMORANDUM: DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC
`HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`DATE:
`
`TO:
`
`FROM:
`
`
`
`15-SEP-2009
`
`N200533 File
`
`Craig M. Bertha, Ph.D.
`Chemistry Reviewer
`ONDQA, Division III, Branch VIII
`
`
`THROUGH: Prasad Peri, Ph.D.
`
`
`Acting Branch Chief
`
`
`ONDQA, Division III, Branch VIII
`
`SUBJECT: Update on Establishment Evaluation Request for N200533 Nucynta™
`(tapentadol) Extended Release Tablets); CMC recommendation
`
`
`SUMMARY:
`
`The Office of Compliance issued an overall recommendation of ACCEPTABLE for the
`application on 15-SEP-2010.
`
`RECOMMENDATION: As per CMC review #3, the application was considered to be
`approvable, considering that there was no recommendation from the Office of Compliance, and
`that there was an outstanding consult on the IVIVC models used for bridging various
`formulations, and the dissolution method and acceptance criteria.
`
`Although the Office of Compliance has given an ACCEPTABLE recommendation for the
`application, from a biopharmaceutics perspective, there remain deficiencies that were addressed
`in the review from Dr. S. Suarez Sharp of 20-AUG-2010. See review for complete details, but in
`summary, the applicant’s IVIVC models were not considered to be supportive for bridging of
`clinical batch formulations to the to-be-marketed formulations. Reconstructed IVIVC models
`resubmitted by the applicant on 23-JUL-2010, are still unacceptable as they contain terms that
`have no mechanistic foundation. Also the models that used the individual subject concentrations
`failed external validation which is considered to be an indication of lack of model robustness.
`Lastly, the proposed dissolution acceptance criteria were based on the IVIVC models, thus the
`criteria are in need of revision. Considering these remaining biopharmaceutics issues, the overall
`CMC recommendation is that the application is approvable.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_______________________________
`Craig M. Bertha, Ph.D.
`CMC Reviewer, ONDQA
`
`

`

`p. 2
`
`EES Status and CMC Recommendation
`
`N200533
`
`
`
`
`cc:
`OND/DAAP/DChiapperino
`ONDQA/DIV 3/CBertha/15-SEP-2010
`ONDQA/DIV 3/PPeri
`ONDQA/DIV3/DChristodoulou
`ONDQA/SSharp-Suarez
`OAP/DAVP/DLee
`OND/DPARP/EBrodsky
`
`

`

`Application
`Type/Number
`--------------------
`NDA-200533
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`ORTHO MCNEIL
`JANSSEN
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`TAPENTADOL
`
`---------------------------------------------------------------------------------------------------------
`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
`09/15/2010
`
`PRASAD PERI
`09/15/2010
`I concur
`
`

`

`
`
`CHEMISTRY REVIEW
`
`NDA 200533
`
`
`Nucynta™ (tapentadol) Extended Release Tablets
`
`
`Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`
`
`
`
`
`Craig M. Bertha, Ph.D.
`Office of New Drug Quality Assessment/Division I/Branch II
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`I. 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
`
`HI. Administrative ........................................................................................................................... 8
`
`A. Reviewer’s Signature........................................................................................................................ 8
`
`B. Endorsement Block........................................................................................................................... 8
`
`C. CC Block.......................................................................................................................................... 8
`
`Chemistry Assessment .............................................................................................9
`
`Page 2
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 200533
`
`2. REVIEW #: 3
`
`3. REVIEW DATE: 08—MAY—2010
`
`4. REVIEWER: Craig M- Bertha, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`30-Nov-2009
`ll-MAR—2010
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 5) Reviewed
`
`30-APR—2010
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`Original
`Amendment
`
`Document Date
`
`Amendment
`
`Name: Ortho-McNeil-Janssen Pharmaceuticals. Inc.
`
`Johnson & Johnson Pharmaceutical Research &
`
`Development. L.L.C.
`1125 Trenton-Harbourton Road. PO. Box 200
`Titusville. NJ 08560-0200
`
`Address:
`
`On behalf of
`
`Ortho—McNeil-Janssen Pharmaceuticals, Inc.
`1125 Trenton-Harbourton Road, PO. Box 200
`Titusville. NJ 08560—0200
`
`Representative: Kathleen F. Dusek, RPh. RAC. Assoc. Director, Reg. Afiairs
`
`Page 3
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Telephone:
`
`609-73 0-27 19
`
`8. DRUG PRODUCT NANHE/CODE/TYPE:
`
`a) Proprietary Name: Nucyntan‘
`b) Non-Proprietary Name (USAN): tapentadol
`c) Code Name/# (0NDQA only): R33 1333, CG5503, 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:
`
`analgesic; tapentadol is a centrally
`acting opioid compound and is proposed for
`the treatment of chronic pain
`
`11. DOSAGE FORM:
`
`extended release tablets
`
`12. STRENGTH/POTENCY: 50, 100, 150, 200, and 250 mg tapentadol (as free
`base)/tablet
`
`13. ROUTE OF ADMINISTRATION: oral
`
`14. Rx/OTC DISPENSED:
`
`_)_(._RX
`
`OTC
`
`15. SPOTS [SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM 2:
`
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`Page 4
`
`

`

`‘.«FI\
`m: I
`
`CHEMISTRY REVIEW
`
`Chemis1Iy Review Data Sheet
`
`‘-A'l\
`E m: I
`
`16- CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`
`
`Chemical Name:
`
`Molecular formula:
`
`3-[(lR,2R)-3-(dimethylamino)—l-ethyl-2-
`methylpropyl]phenol monohydrochloride
`CMHBNO-HCI
`
`Molecular Weight:
`CAS:
`
`257.80 g/mol; Free base: 221.34 g/mol
`175591-09-0
`
`l7. RELATED/SUPPORTING DOCUMENTS:
`
`A.SllI Io I'_DMFS:
`mm mm law-3!-
`
`1
`
`1
`
`DATE REVIEW
`
`sums
`
`|-- ”DEE-mm” -
`
`'I-W‘llug 4
`
`Tapmndol HCl (M31333
`Drug Subsunce
`
`Adequate
`
`09—APR-2008
`
`Reviewed for
`N22304 (Nucyma
`Tablets)
`
`Page 5
`
`

`

`
`
`Chemistry Review Data Sheet
`
`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 — Sufl'lcient 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:
`
`ITEM
`mm REFERENCED
`
`STATUS
`
`DATE REVIEW
`COMPLETED
`
`
`
`COMMENTS
`
`C. Related Documents:
`
`“—W
`
`APPLICATION
`
`“ °"“°'M°N°“'
`
`22304
`
`Ortho-McNeil-
`Janssen
`
`NDA for immediate release Nucynta (tapentadol)
`Tablets for treatment of moderate to severe vain
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`
`STATUS/
`COMNIENTS
`REVIEWER
`FORVVAATIEDED
`SUBJECT
`CONSULTS
`—————17DEC2009
`Hi
`2>
`
`0NDQA Biophann
`
`IVIVC and dissolution
`acc . m ecritcn'a
`
`lo-DEC-2009
`
`Pending/S Sautez,
`
`lA— Seep. 950fCR#l U
`
`OPDRA
`
`iMethods Validation
`
`Microbiolo3
`
`/A— See- .91 ofCR#l
`
`Page 6
`
`

`

`
`
`The Chemistry Review for NBA 200533
`
`The Executive Summagg
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is considered approvable, as there is an outstanding consult for
`the IVIVC and dissolution method/acceptance criteria with the biopharmaceutics
`team in ONDQA. Also note that the facility inspections are outstanding and the
`above CMC recommendation does not incorporate any potential facility
`inspection issues.
`
`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, Nucynta ER (tapentadol) Extended Release Tablets is a solid
`dosage form with strengths of 50, 100, 150, 200, and 250 mg (as tapentadol free-
`base), intended for oral administration. It is indicated for the treatment of chronic
`pain, and is packaged in high-density polyethylene bottles fitted with child
`resistant closures, each containing 60 tablets (for all strengths). Each strength is
`also packaged in cartons, said to be for hospital use only, that contain ten blister
`cards each containing ten tablets (100 count . The dru
`roduct formulation
`
`consists of tapentadol h drochlorid
`
`
`
`
`
`hypromellosefl andpolyeth lene
`polyeth leneoxide
`The formulationalso containsasmallamountb. The
`
`
`
`
`exci ient com nents.
`
`ro ortional with re
`
`ect to the active and
`
`
`
`proprietary coatings of different colors for each strength and each is also
`imprinted with a unique alphanumeric code. It is important to note that the
`commercial products (tamper-resistant formulations, TRF), described above,
`differ from that which were studied in the phase 3 clinical Ilials (PR2
`formulations). The applicant is using a BA/BE and IVIVC approach to link the
`formulations.
`
`Page 7
`
`

`

`
`
`CHEMISTRY REVIEW
`
`‘ .A'l‘
`
`E m: s
`
`The drug substance, tapentadol h drochloride, is a chiral o ioid co
`
`und
`
`“assess chemicalsynthesisflIt has already been approved for use to treat moderate to severe
`
`ain in an immediate release formulation from the same a
`
`licant.
`
`
`
`B. Description of How the Drug Product is Intended to be Used
`
`The labeling indicates that the drug product is to be used by patients 18 years of
`age or older for the management of moderate to severe chronic pain. The product
`is an opioid analgesic that is to be used around-the—clock for an extended period
`of time. The daily dose is said to be 100 to 250 mg twice daily (taken at 12 hour
`intervals), with or without food. Note the 50 mg strength is used for opioid—naive
`patients. There are no unusual storage conditions recommended in the labeling
`and the stability data do not suggest that any such conditions are necessary. The
`label does indicate that patients should protect the drug product from moisture.
`Currently the applicant proposes a 24 month expiration dating period for the drug
`product in both the bottle and blister packaging presentations. The currently
`available stability data support 24 month expiry periods for both the bottled and
`blister packaged product.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`NIA
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Craig M. Bettina, PhD/Chemistry Reviewer: 08-MAY-2010
`
`Prasad Peri, Ph.D./Acting Branch Chief
`
`C. CC Block
`
`DChristodoulou/PAL
`
`DChiappaino/PM
`
`Page 8
`
`

`

`Application
`Type/Number
`--------------------
`NDA-200533
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`ORTHO MCNEIL
`JANSSEN
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`TAPENTADOL
`
`---------------------------------------------------------------------------------------------------------
`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
`05/06/2010
`
`PRASAD PERI
`05/06/2010
`I concur
`
`

`

`
`
`CHEMISTRY REVIEW
`
`NDA 200533
`
`
`Nucynta™ (tapentadol) Extended Release Tablets
`
`
`Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`
`
`
`
`
`Craig M. Bertha, Ph.D.
`Office of New Drug Quality Assessment/Division I/Branch II
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................7
`
`I. 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
`
`HI. Administrative ........................................................................................................................... 8
`
`A. Reviewer’s Signature........................................................................................................................ 8
`
`B. Endorsement Block........................................................................................................................... 8
`
`C. CC Block.......................................................................................................................................... 8
`
`Chemistry Assessment .............................................................................................9
`
`Page 2
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 200533
`
`2. REVIEW #: 2
`
`3. REVIEW DATE: l8—MAR—2010
`
`4. REVIEWER: Craig M- Bertha, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`30-Nov-2009
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 5) Reviewed
`
`ll—MAR—2010
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`Oliginal
`
`Document Date
`
`Amendment
`
`Name: Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`
`Johnson & Johnson Pharmaceutical Research &
`
`Development. L.L.C.
`1125 Trenton-Harbourton Road. PO. Box 200
`Titusville. NJ 08560-0200
`
`Address:
`
`On behalf of
`
`Ortho—McNeil-Janssen Pharmaceuticals, Inc.
`1125 Trenton—Haibourton Road, PO. Box 200
`Titusville. NJ 08560—0200
`
`Representative: Kathleen F. Dusek, RPh. RAC. Assoc. Director, Reg. Afiairs
`
`Telephone:
`
`609-73 0—27 19
`
`Page 3
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`

`

`
`
`Chemistry Review Data Sheet
`
`8. DRUG PRODUCT NANHE/CODE/TYPE:
`
`a) Proprietary Name: NucyntaTM
`b) Non-Proprietary Name (USAN): tapentadol
`c) Code Name/# (0NDQA only): R33 1333, CG5503, 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:
`
`analgesic; tapentadol is a centrally
`acting opioid compound and is proposed for
`the treatment of chronic pain
`
`11. DOSAGE FORM:
`
`extended release tablets
`
`12. STRENGTH/POTENCY: 50, 100, 150, 200, and 250 mg tapentadol (as free
`base)/tablet
`
`13. ROUTE OF ADMINISTRATION: oral
`
`14. Rx/OTC DISPENSED:
`
`_)_(._RX
`
`OTC
`
`15. SPOTS [SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM 2:
`
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`Page 4
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`

`

`a...“
`um: I
`
`CHEMISTRY REVIEW
`
`Chemis1Iy Review Data Sheet
`
`‘-A'l\
`E m: I
`
`16- CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`
`
`Chemical Name:
`
`Molecular formula:
`
`3-[(lR,2R)-3-(dimethylamino)—l-ethyl-2-
`methylpropyl]phenol monohydrochloride
`CMHBNO-HCI
`
`Molecular Weight:
`CAS:
`
`257.80 g/mol; Free base: 221.34 g/mol
`175591-09-0
`
`l7. RELATED/SUPPORTING DOCUMENTS:
`
`A.SllI Io I'_DMFS:
`Imm mm m ms,
`
`
`
`|-- nDFE-mm -
`
`
`
`
`
`”A“W —com
`
`'I-Wdflg —Tapmladol HCl (11331333
`
`Am 09-APR-2008
`
`Reviewedfiot
`N223o4 (Nucyma
`Tablets)
`
`Page 5
`
`

`

`
`
`Chemistry Review Data Sheet
`
`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 — Sufl'lcient 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:
`
`ITEM
`mm REFERENCED
`
`STATUS
`
`DATE REVIEW
`COMPLETED
`
`
`
`COMMENTS
`
`C. Related Documents:
`
`“—W
`
`APPLICATION
`
`“ °"“°'M°N°“'
`
`22304
`
`Ortho-McNeil-
`Janssen
`
`NDA for immediate release Nucynta (tapentadol)
`Tablets for treatment of moderate to severe vain
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`
`STATUS/
`COMNIENTS
`REVIEWER
`FORVVAATIEDED
`SUBJECT
`CONSULTS
`—————17DEC2009
`Hi
`2>
`
`0NDQA Biophann
`
`IVIVC and dissolution
`acc . m ecritcn'a
`
`lo-DEC-2009
`
`Pending/S Sautez,
`
`lA— Seep. 950fCR#l U
`
`OPDRA
`
`iMethods Validation
`
`Microbiolo3
`
`/A— See- .91 ofCR#l
`
`Page 6
`
`

`

`fl-A'H
`m: .
`
`CHEMISTRY REVIEW
`
`fins-h
`_ m: ‘
`
`The Chemistry Review for NBA 200533
`
`The Executive Summafl
`
`1.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is recommended for approval, however, the recommendation
`fi'om the Oflice of Compliance is pending. In addition, there is an outstanding
`consult for the IVIVC and dissolution method/ace
`tance criteria with the
`
`bio harmaceutics team in 0ND A.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None at this time.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug product, Nucynta ER (tapentadol) Extended Release Tablets is a solid
`dosage form with strengths of 50, 100, 150, 200, and 250 mg (as tapentadol free-
`base), intended for oral administration. It is indicated for the treatment of chronic
`pain, and is packaged in high-density polyethylene bottles fitted with child
`resistant closures, each containing 60 tablets (for all strengths). Each strength is
`also packaged in cartons, said to be for hospital use only, that contain ten blister
`cards each containing ten tablets (100 count . The dru
`roduct formulation
`
`consists of tapentadol h drochloride
`
`polyeth lene oxide
`hypromellose
`and polyeth lene
`
`e ormulationalsocontamsasmallamounti. The
`
`
`t to the active and
`
`
`
`proprietary coatings of difi'erent colors for each strength and each is also
`imprinted with a unique alphanumeric code. It is important to note that the
`commercial product (tamper-resistant formulations, TRF), described above,
`differs from that which was studied in the phase 3 clinical trials (PR2
`formulations). The applicant is using a BA/BE approach to link the formulations.
`
`The tablet cores are coated with
`
`Page 7
`
`

`

`
`
`CHEMISTRY REVIEW
`
`‘ .m.“
`
`E at: ‘
`
`The drug substance, tapentadol h drochloride, is a chiral o ioid co
`
`und
`
`“minedb chemicalsynmesifl
`
`It has already been approved for use to treat moderate to severe
`ain in an immediate release formulation from the same a
`licant.
`
`
`
`B. Description of How the Drug Product is Intended to be Used
`
`The labeling indicates that the drug product is to be used by patients 18 years of
`age or older for the management of moderate to severe chronic pain. The product
`is an opioid analgesic that is to be used around-the—clock for an extended period
`of time. The daily dose is said to be 100 to 250 mg twice daily (taken at 12 hour
`intervals), with or without food. As such, it is unclear why the application
`includes a 50 mg strength dosage form. There are no unusual storage conditions
`recommended in the labeling and the stability data do not suggest that any such
`conditions are necessary. The label does indicate that patients should protect the
`drug product fi'om moisture. Currently the applicant proposes a 24 month
`expiration dating period for the drug product in both the bottle and blister
`packaging presentations. The currently available stability data, along with the
`statistical analyses provided for the moisture content stability data for blister
`packaged drug product (see response to comment 21 in this review), support 24
`month expiry periods for both the bottled and blister packaged product.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`N/A
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Craig M. Benin, PhD/Chemistry Reviewer: l8-MAR-2010
`
`Prasad Peri, Ph.D./Acting Branch Chief
`
`C. CC Block
`
`DChristodoulou/PAL
`
`DChiapperino/PM
`
`
`
`Page 8
`
`

`

`Application
`Type/Number
`--------------------
`NDA-200533
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`ORTHO MCNEIL
`JANSSEN
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`TAPENTADOL
`
`---------------------------------------------------------------------------------------------------------
`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
`03/18/2010
`
`PRASAD PERI
`03/18/2010
`I concur
`
`

`

`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`
`
`NDA 200533
`
`
`Nucynta™ (tapentadol) Extended Release Tablets
`
`
`Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`
`
`
`Craig M. Bertha, Ph.D.
`Office of New Drug Quality Assessment/Division I/Branch II
`
`for
`
`Division of Anesthetics, Analgesics, and Rheumatoid
`Products
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
`
`The Executive Summary .........................................................................................9
`
`I. Recommendations ...................................................................................................................... 9
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 9
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 9
`
`II. Summary of Chemistry Assessments.........................................................................................9
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 9
`
`B. Description of How the Drug Product is Intended to be Used ....................................................... 10
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 10
`
`HI. Administrative ......................................................................................................................... 10
`
`A. Reviewer’s Signature...................................................................................................................... 10
`
`B. Endorsement Block......................................................................................................................... 10
`
`C. CC Block........................................................................................................................................ 10
`
`Chemistry Assessment .......................................................................................... l 1
`
`Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2:
`I.
`Body Of Data ......................................................................................................... 11
`
`S DRUG SUBSTANCE [tapentadol HCl, Janssen] ...................................................................... 11
`
`P DRUG PRODUCT [tapentadol extended release tablets] .......................................................... 12
`
`Pl Description and Composition of the Drug Product [tapentadol extended release tablets] ............. 12
`
`P2 Pharmaceutical Development [tapentadol extended release tablets] .............................................. 14
`
`P3 Manufacture [tapentadol extended release tablets] ........................................................................ 35
`
`R4 Control of Excipients [tapentadol extended release tablets] .......................................................... 40
`
`P5 Control of Drug Product [tapentadol extended release tablets] ...................................................... 43
`
`R6 Reference Standards or Materials [tapentadol extended release tablets] ....................................... 68
`
`R7 Container Closure System [tapentadol extended release tablets] ................................................... 68
`
`Page 2
`
`

`

`, ”‘5"
`
`CHEMISTRY REVIEW
`
`f'F'X
`
`P.8 Stability [tapentadol extended release tablets] ............................................................................... 72
`
`A APPENDICES ........................................................................................................................... 91
`
`Al Facilities and Equipment (biotech only) ........................................................................................ 91
`
`A2 Adventitious Agents Safety Evaluation ......................................................................................... 91
`
`A3 Novel Excipients ........................................................................................................................... 91
`
`R REGIONAL INFORMATION .................................................................................................. 92
`
`R1 Executed Batch Records ................................................................................................................. 92
`
`R2 Comparability Protocols ................................................................................................................. 92
`
`R3 Methods Validation Package .......................................................................................................... 92
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ....................................93
`
`A. Labeling & Package Insert ..................................................