CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-030
`
`CHEMISTRY REVIEWg S)
`
`

`

`MEMORANDUM
`
`Date:
`
`September 23, 2008
`
`To:
`
`NDA 22-030
`
`From: Elaine Morefieid, Ph.D.
`Division Director
`
`Pre-marketing Assessment Division I
`ONDQA
`'
`
`Subject: Tertiary review of ONDQA recommendation for NDA 22-030 Toviaz®
`(fesoteridine filmarate) Extended Release Tablets, by Pfizer, Inc.
`
`NDA 22-030 is for Toviaz® (fesoteridine fumarate) extended release tablets for the
`treatment of overactive bladder with symptoms of urge urinary incontinence, urgency,
`and urinary frequency.
`
`This NDA has provided sufficient CMC information to assure the identity, strength,
`purity, and quality of the drug product. All facilities involved are in compliance with
`cGMP, and labels have adequate information as required. Therefore, from a CMC
`perspective, this NDA is recommended for approval.
`
`I believe that there are adequate
`I have assessed the ONDQA review of NDA 22-030.
`manufacturing procedures and controls for production of a quality product.
`I concur with
`the approval recommendation fiom a CMC perspective.
`
`Appears This Way
`0“ Original
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Elaine Morefield
`10/16/2008 04:18:18 PM
`CHEMIST
`
`

`

`
`
`Chemistry Review Data Sheet
`
`NDA 22-030
`
`TOVIAZ
`
`(Fesoterodine fumarate)
`‘ {Trade name is not finalized}
`
`Extended release tablets
`
`Pfizer, Inc.
`
`Division of Reproductive and Urologic Products
`
`Rajiv Agarwal
`
`DIVISION OF PRE-MARKETING DRUG QUALITY ASSESSMENT
`I
`(Branch III, Division II)
`
`Page 1 01°31
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`.
`
`1. NDA #
`2. REVIEW #:
`3. REVIEW DATE:
`4. REVIEWER:
`5. PREVIOUS DOCUMENTS:
`
`22-030
`2
`10-AUG-2008
`Rajiv Agarwal
`
`Original
`Amendment
`Amendment ‘
`Amendment
`
`Amendment
`Amendment
`Amendment
`CMC review # 1
`Approvable letter
`
`6.
`
`SUBMISSION(S) BEING REVIEWED:
`
`.
`
`Submission} 3) Reviewed
`
`Complete Response
`Amendment
`Amendment
`
`7. NAME & ADDRESS 'OF APPLICANT:
`
`17—MAR-2006
`15-MAY-2006
`03 -AUG-2006
`06 -OCT-2006
`16-NOV-2006
`22-Nov-2006
`l l-JAN-2007
`1 9-JAN -2007
`25—JAN—2007
`
`MIME
`01-MAY-2008
`1 9-MAY-2008
`1 8-]UN -2008
`
`Name:
`
`Pfizer, Inc.
`
`Address:
`
`235 East 42“d Street, New York, NY 10017
`
`Representative: - Alan McEmber, Director, Worldwide Regulatory
`
`Telephone:
`
`212-733—0081
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):
`c) Code Name/# (ONDQA only):
`d) Chem. Type/Submission Priority (ONDQA only):
`
`TOVIAZ
`fesoterodine fumarate
`SPM 907
`
`0 Chem. Type:
`
`1
`
`0 Submission Priority: Standard
`
`Page 2 of31
`
`

`

`
`
`Chemistry Review Data Sheet
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`505 (b) (1)
`
`10. PHARMACOL. CATEGORY:
`
`For the treatment of overactive bladder with symptoms of urge
`urinary incontinence, urgency, and urinary frequency
`
`11. DOSAGE FORM:
`
`Tablet (Extended release)
`
`12. STRENGTH/POTENCY:
`
`4 and 8 mg
`
`13. ROUTE OF ADMINISTRATION:
`
`Oral
`
`14. Rx/OTC DISPENSED:
`
`_x_Rx
`
`_OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM [:
`SPOTS product — Form Completed
`
`x Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name:
`
`Isobut ric acid-2- R-3-diiso ro
`
`
`
`
`Molecular Formula:
`
`C3“)H.,.NO7
`
`Molecular weight:
`
`527.66 (salt), 411.59 (base)
`
`Page 3 of31
`
`

`

`
`
`Chemistry Review Data Sheet
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`DMF #
`'
`
`
`
`
`
`HOLDER
`
`ITEM
`REFERENCED
`
`1
`
`CODE
`
`2
`
`STATUS
`
`
`
`DATE REVIEW
`COMPLETED
`16—JUL~2004
`
`
`
`Adequate
`
`l7—MAR-2003
`
`Adequate
`
`02-SEP-2003
`
`COMMENTS
`Li-Shan Hsieh,
`NDA 21—743
`
`Young-dc Lu,
`- NDA 21—545
`
`
`
`
`33(4)
`
`'
`
`
`
`
`3
`
`Adequate
`
`.
`11-MAR-2005
`
`20-0CT-2003
`
`
`
`
`
`
`
`NDA 21-621
`Gene W.
`Holbert, NDA
`
`Ramesh Sood,
`NDA 20-334 r ‘-'
`
`1 Action codes for DMF Table:
`l — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 —- Reviewed previously and no revision since last review
`4 ~ Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 -— Other (explain under "Comments")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need to
`be reviewed)
`
`B. Other Documents:
`0
`IND 51,232
`0
`CMC review # 1: l9-JAN-2007
`
`'18. STATUS:
`ONDQ'A:
`
`CONSULTS/ CMC
`RELATED REVIEWS
`
`DMEPA
`
`
`
`
`
`
`
`
`
`
`
`
`‘
`
`RECOMMENDATION
`
`A
`
`
`
`DATE
`15—JUL-2008
`
`REVIEWER
`Office of Compliance
`
`Categorical exclusion Granted
`
`19-]AN-2007
`
`Dr. Ra‘iv Agarwal
`
`
`
`
`
`
`
`
`
`Page 4 of3l
`
`

`

`NDA 22—030
`
`Applicant: Pfizer
`
`The Chemistry Review for NDA 22—030
`
`The Executive Summary
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`This NDA has provided sufficient CMC information to assure the identity, strength, purity, and
`quality of the drug product. All facilities involved are in compliance with cGMP, and labels have
`adequate information as required. Therefore, from a CMC perspective, this NDA is recommended
`for “Approval”.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, ifApprovable
`
`None
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description ofthe Drug Prodnct(s) and Drug Substance(s)
`
`Drug product:
`
`TOVIAZ (fesoterodine fumarate), 4 mg and 8 mg, is an extended release tablet, which is either light blue (4
`mg) or blue (8 mg) in color, oval in shape, and film coated. Fesoterodine is immediately de—esterified to its
`active metabolite (a diol), R—Z—(3-diisopropylamino-1-phenylpropyl)-4—hydroxymethyl-phenol (SPM 7605).
`
`This product is indicated for the treatment of overactive bladder with symptoms of urge urinary
`incontinence, urgency, and frequency. The tablets are manufactured by Schwarz Pharma Manufacturing
`lnc., in Germany and tested, packaged and labeled by Schwarz Pharma, IN, USA. The final
`recommendation from the Office of Compliance for the drug product manufacturing and testing sites is
`acceptable.
`
`The extended release tablet system of fesoterodine tablet is a
`
`\
`
`\\
`
`
`The quality of the tablets is controlled by the following tests:
`
`.
`_
`All the respective acceptance criteria are deemed
`
`satisfactory except for the acceptance criteria for impurities.
`
`
`As per ICH Q6A, decision tree # 2, Division recommended and applicant accepted that the acceptance
`critei‘ia ofthe specified impurities ‘ M~\——\T
`WFW details regarding this section, refer to CMC review 1
`dated I9-JAN-2007).
`
`Fesoterodine fumarate extended release tablets were developed with '/ engraved on one side of the
`tablets. In the Complete Response, the engraving has been modified for the commercial formulation to
`take into account the change in product ownership. For lower strength tablets (4 mg), “FS” will be
`engraved on one side and “FT” will be engraved on one side of the 8 mg strength tablets.
`
`

`

`NDA 22-030
`
`Applicant: Pfizer
`
`To support the change in engraving, comparative dissolution testing was performed in the specified release
`media (Phosphate buffer pH 6.8) between the proposed commercial formulations with “FS” or “FT”
`engraving (4 mg and 8 mg strengths, respectively) and the current formulations with / engraving (4 mg
`and 8 mg strengths). The data showed that tablets engraved with “FS” (4 mgstrength tablets) or “FT” (8
`mg strength tablets) show equivalent dissolution to those engraved with / i. The change in engraving is
`acceptable.
`
`um
`
`Throughout clinical development, the sustained release formulations were used. The basic composition of
`all tablet formulations and the basic manufacturing process remained the same.
`”“thx
`
`M4)
`
`M4)
`
`t “
`
`\
`a)
`
`v
`
`.
`
`The to—be-marketed tablets for each strength will be manufactured by the process usingR
`uses the formulation “F” which was used in the phase 3 clinical trails.
`
`Subsequent to the change of product ownership to Pfizer, additional packaging presentations K...
`cc bottles) have been identified in the current submission. The applicant added 5 new DMFs from different
`suppliers related to the w—————-————-—-———_"‘_—"Cap and bottles. The
`information pertaining to their use in packaging ot’a solid oral dosage form is reviewed previously and was
`found adequate.
`
`The tablets are packaged in two different packaging configurations (bottles and blisters). Bottles ._ V
`
`/ :re madeof“ and contair/' 30 and 90
`tablets. respectively. The 5,...“
`is used for all bottle sizes. Bottles are secured with
`
`cap F—-——-——-——.‘
`
`,
`
`13(4)
`
`.
`I'M Depending on the size of the bottle, I /‘ ,.
`N For physician’s samples, me blister contains 14 tablets per card/
`fl Although the applicant did not state that the physician samples are
`child resistant, it appears that the packaging in tear/push blister will make the blisters packages child
`resistant (16 CFR 1700). Stability data (drug product) supports their usage in the drug product. The
`presented packaging configuration also meet the USP <661> compatibility and suitability requirements.
`
`Based on the real time data, the applicant is requesting a 24 months of shelf life. During the first review
`cycle, based on the stability studies on primary batches, it is determined that a 24 months of expiration date
`may be granted for the product packaged in bottles and blisters. Based on the stability characteristics of the
`drug product, the applicant proposed and FDA accepted .the storage condition to be “Store at 20° to 25°C
`(68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room
`Temperature]. Protect from moisture”.
`
`A final decision on the trade name “TOVIAZ” has not been made by DMEPA.
`
`Drug Substance:
`
`Fesoterodine fumarate is a new molecular entity and is manufactured by Schwarz & Company in Shannon,
`Ireland. Fesoterodine fumarate is the dextrorotary enantiomer of a derivative of 3,3-diphenylpropylamine
`and is fix—— a diol, which is an active metabolite. The structure of drug
`substance includes one chiral center and its melts at ~——~Both salt and base are freely soluble in various
`
`

`

`NDA 224030
`
`‘
`
`Applicant: Pfizer
`
`buffers. The salt is freely soluble r'f in water -W
`. mg/ml). At a temperature of:d’ the pKa—value of this drug substance is 'M
`
`The quality of the drug substance is controlled by specification set by the manufacturer, which includes, .
`
`<
`
`deemed satisfactory.
`
`/\ They are
`
`h<4l
`
`Drug substance, when stored at accelerated conditions /M
`
`
`The final recommendation from the Office of Compliance for Schwarz, Shannon, Ireland site is
`ACCEPTABLE (Attachment-l).
`'
`
`The applicant is requesting a / of re-test period. Granted.
`
`B. Description ofHow the Drug Product is Intended to be Used
`
`TOVIAZ (fesoterodine fumarate) is an extended-release tablet for once-daily oral administration.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`This NDA provided adequate information on the raw material controls, manufacturing process,
`specifications, andcontainer/closure. It also provided sufficient stability data to assure identity, strength,
`purity and quality of the drug product during the shelf life. The Office of Compliance has issued an
`“Acceptable” overall recommendation (Attachment-1) for all the facilities involved on 15-JUL-2008.
`Labels have required information.
`"
`
`The DMEPA has not made a final decision on the proposed trade name. The absence of an approved trade
`name is not an approvability issue [21 CFR 201.57 (a) (2)].
`
`III. Administrative
`
`A. Reviewer’s Signature: Captured electronically in DFS
`
`B. Endorsement Block: RAgarwaI/ MRhee
`
`C. CC Block: EMorefield/DFChristner/CHayes
`
`

`

`Q?) Page(s) Withheld
`
`é Trade Secret / Confidential (b4)
`
`_—
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`Withheld TrackNumber: Chemistry- 1
`
`

`

`---------.u—nu-nu--------------------------------------------------------------------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Elaine Morefield
`1/22/2007 06:43:27 PM
`CHEMIST
`
`

`

`
`
`Chemistry Review Data Sheet
`
`NDA 22-030
`
`“R
`(Fesoterodine fumarate)
`
`33(4)
`
`Extended release tablets
`
`Schwarz Biosciences, Inc.
`
`Division of Reproductive and Urologic Products
`
`Rajiv Agarwal
`
`DIVISION OF PRE-MARKETING DRUG QUALITY ASSESSMENT
`(Branch III, Division II)
`
`Page 1 of 61
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`Document Date
`
`17-MAR-2006
`15-MAY-2006
`03 -AUG-2006
`06-OCT-2006
`16-NOV-2006
`22—Nov-2006
`1 1-JAN—2007
`
`22—030
`1
`.
`18-JAN-2006
`
`Rajiv Agarwal
`N/A
`
`. NDA#
`. REVIEW #:
`. REVIEW DATE:
`. REVIEWER:
`. PREVIOUS DOCUMENTS:
`
`1 2 3 45
`
`SUBMISSION(S) BEING REVIEWED:
`
`Submission( 3) Reviewed
`
`Original
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Schwarz Biosciences, Inc.
`
`Address: 8010 Arco Corporate Drive, Suite 100, Raleigh, NC 27617
`
`Representative: Alan Blumberg, Sr. Director, Regulatory Affairs
`
`Telephone:
`
`919-767—2513
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):
`c) Code Name/# (ONDQA only):
`d) Chem. Type/Submission Priority (ONDQA only):
`
`49——
`
`fesoterodine fiimarate
`SPM 907
`
`0 Chem. Type:
`
`1
`
`0 Submission Priority: Standard
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`505 (b) (1)
`
`10. PHARMACOL. CATEGORY:
`
`For the treatment of overactive bladder with symptoms of urge
`urinary incontinence, urgency, and urinary frequency
`
`l 1. DOSAGE FORM:
`
`Tablet (Extended release)
`
`Page 2 of 61
`
`

`

`
`
`Chemistry Review Data Sheet
`
`12. STRENGTH/POTENCY:
`
`4 and 8 mg
`
`13. ROUTE OF ADMINISTRATION:
`
`Oral
`
`_
`
`l4. Rx/OTC DISPENSED:
`
`x Rx
`
`OTC
`
`15. SPO'I‘S (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`x Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name:
`
`
`Isobu ric acid-Z- R-3-diiso r0
`
`
`hydrogen fumarate
`
`.
`a)
`H0,/’\“\/>
`. (Kr/Y
`:
`KN; //\
`l/ \
`
`H c
`
`Hezc’D/COZ'
`
`Molecular Formula:
`
`C30H41N07
`
`Molecular weight:
`
`527.66 (salt), 411.59 (base)
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
`
`
`
`1
`
`STATUSZ
`
`ITEM
`
`
`
`
`CODE
`HOLDER
`REFERENCED
`
`N/A
`/ ---
`
`
`
`
`
`DATE REVIEW
`COMPLETED
`
`
`
`COMMENTS
`Sufficient
`information in
`
`the NDA
`
`
`Dr. L-S Hsieh
`
`for NDA 21-743
`
`
`
`
`Dr. L-S Hsieh
`
`for NDA 21-743
`
`
`
`
`33(4)
`
`’
`
`
`
`
`
`26mm
`
`Page 3 of 61
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Adequate
`.
`
`Dr. R. Uppoor
`for NDA 21-290
`
`
`
`~
`
`'
`
`_
`
`"
`
`.
`
`.
`
`.
`
`.
`
`Adequate
`
`15-JUN-2000
`
`N/A
`
`Dr. K. Swiss for
`NDA 21-1 65
`
`Sufficient
`information in
`the NDA
`
`Adequate
`
`27-JUL—2004
`
`for ND/ "‘
`
`Dr. S. Pope for
`NDA 21-663
`
`Adequate
`
`Adequate
`
`N/A
`
`25-AUG-2004
`
`04-NOV-2005 - Dr. C-H Niu for
`NDA'
`Dr. A. Schroeder
`for NDA 21-585
`Sufficient -
`information in
`the NDA
`
`93(4) _
`
`' 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")
`
`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:
`
`IND 51,232
`EOP2 meeting l3-JUL-O4
`Pre NDA (CMC) 18-NOV-OS
`74-day letter dated 9—JUN-2006
`CMC 1R letter: l3—DEC—2006
`
`0
`
`O
`
`CMC labeling IR: 17-JAN—2007
`18. STATUS:
`ONDQA:
`
`CONSULTS/ CMC
`RELATED REVIEWS
`
`
`
`RECOMMENDATION
`
`
`
`9-N0V-2006
`
`Office of Comliance
`
`REVIEWER
`
`
`
`
`
`
`
`
`
`
`
`
`EA
`Categorical exclusion Granted
`
`
`
`
`
`Methods Validation
`
`The method validation package will be
`
`sent to and validated by FDA laboratories.--
`
`Dr. Rajiv Agarwal
`
`Page 4 of61
`
`

`

`
`
`Chemistry Review Data Sheet
`
`The Chemistry Review for NBA 22-030
`
`The Executive Summary
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`This application is approvable from Chemistry, Manufacturing and Control standpoint based on
`the WITHHOLD recommendation from the Office of Compliance for the Drug substance
`manufacturing site in Ireland, and some labeling issues.
`'
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, ifApprovable
`
`None
`
`11.
`
`Summary of Chemistry Assessments
`
`A. Description ofthe Drug Product(s) and Drug Substance(s)
`
`Drug product:
`
`—- (fesoterodine fumarate), 4 mg and 8 mg, is an extended release tablet, which is either light blue
`(4 mg) or blue (8 mg) in color, oval in shape, fllm coated and engraved on one side with SP. Fesoterodine
`is immediately de—esterified to its active metabolite (a diol), R-Z—(3-diisopropylamino-l-phenylpropyl)—4-
`hydroxymethyl-phenol (SPM 7605), which is a muscarinic receptor antagonist.
`
`This product is indicated for the treatment of overactive bladder. The tablets are manufactured by Schwarz
`Pharma Manufacturing Inc., in Germany and tested, packaged and labeled by Schwarz Pharma, IN,
`USA. The final recommendation from the Office of Compliance for the drug product manufacturing and
`testing sites is acceptable.
`'
`
`The extended release tablet system of fesoterodine tablet is a
`
`2
`
`\\
`
`-._
`
`The quality of the tablets is controlled bv tests:w
`
`All the respective acceptance criteria are deemed satisfactory
`except for the acceptance criteria of impurities.WW
`
`As per ICH
`Q6A, decision tree # 2, Division recommended that the acceptance criteria of the specified impurities be
`
`/
`
`
`
`The applicant did not establish acceptance criteria for chiral purity in drug product but because-.1 ..’-—-\
`
`of the drug substance under the recommended storage conditions, it is acceptable. The drug product is
`
`
`
`,recommended to be stored at V ,.J ,,
`_.____-_..
`
`Page 5 of 61
`
`

`

`NDA 22-030
`
`Applicant: Schwarz
`
`
`
` Mi)
`
`Throughout clinical development, five sustained release formulations were used.- The basic composition of
`all tablet formulations and the basic manufacturing process remained the same.
`
`M4)
`
`M4}?
`
`. L
`
`J
`
`The to-be-marketed tablets for each strength will be manufactured by '
`uses the formulation “F” which was used in the phase 3 clinical trails.
`
`
`.
`
`The tablets are packaged in two different packaging configurations (bottles and blisters). Bottles,
`Ware made of .W contain, 30 and 90 tablets, respectively.
`Whereas the blister contain V. 14 tablets per blister card (for physicians samples). Bottles aresecured
`with _m capM The bottles will
`
`'
`Stability data (drug product) supports their usage in the drug product. The
`presented packaging configuration also meet the USP <661> compatibility and suitability requirements.
`The aluminum/aluminum blisters are for physicians sample only.
`
`,
`
`Sponsor is requesting a 24 months of shelf life. Based on the stability studies on primary batches, 24
`months of expiry date may be granted for the product packaged in bottles and blisters. Based on the
`stability characteristics of the drug product, the applicant proposed and FDA accepted the storage condition
`to be “Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F)
`[see USP Controlled Room Temperature]. Prbtect from moisture”.
`
`The trade name ‘ ‘13 Acceptable to DMETS.
`Drug Substance:
`
`1‘4?
`
`Fesoterodine is a new molecular entity and is manufactured by Schwarz and Company in Shannon, Ireland.
`Fesoterodine fumarate is the dextrorotary enantiomer of a derivative of 3,3—diphenylpropylamine and is
`
`"
`/ a diol, which is an active metabolite. The structure of drug
`substance includes one chiral center and its melts at '/ Both salt and base are freelv soluble in various
`
`buffers. The salt is freely 50% in water‘
`,r—w
`m——~7/
`/‘At a temperature 0’
`he pKa—value of this drug substance is/
`
`The aualitv of the drug substance is controlled by specification set by the manufacturer, which includes,
`a
`/>
`They are
`deemed satisfactory.
`
`but
`
`Brita/strbmance. when stored at accelerated conditions
`ewe.
`
`»
`
`fl>
`
`

`

`NDA 22-030
`
`Applicant: Schwarz
`
`The final recommendation from the Office of Compliance for Schwarz, Ireland site is withhold (see
`Attached 1) because the site is not ready for inspection. In a submission dated ISLMAY-2006, the applicant
`stated the manufacturing site will not be ready for PA] inspection and will likely extend beyond the PA]
`readiness date of July, 2007 as specified in their NDA submission.
`.5.“
`
`The applicant is requesting a“: l of re—test period. Granted.
`
`B. Description ofHow the Drug Product is Intended to be Used
`
`Ky (fesoterodine fumarate) is an extended—release tablet for once-daily oral administration.
`
`h(4)
`
`C.‘ Basisfor Approvability or Not-Approval Recommendation
`
`.
`
`This application is approvable from Chemistry, Manufacturing and Control standpoint based on
`the WITHHOLD recommendation from the Office of Compliance for the Drug substance
`manufacturing site in Ireland, and the following labeling issues which were conveyed to the
`applicant on l7—JAN—2007.
`
`0’ The "X" graphic which precedes the proprietary name should be removed on all labels.
`
`0
`Replace the word ”Trade Name" with
`in the PI and PP].
`o
`In the "How Supplied" section, the NDC #s for the 4 mg and 8 mg blister presentations in the
`PI do not matchthe NDC #3 provided on the blister labels. Please correct the NDC #s so that
`they are the same on both the blister labels and the Pl.
`-
`f?
`
`A
`
`o
`
`‘
`
`h‘4) -
`
`K
`
`III. Administrative
`
`A. Reviewer ’3 Signature: Captured electronically in DFS
`
`B. Endorsement Block: RAgarwal/ MRhee
`
`C. CC Block: EMorefield/Jean Makie/DFChristner
`
`)
`
`

`

`63
`
`Page(s) Withheld '
`
`. X
`
`_———
`
`Trade Secret / Confidential (b4)
`
`.—.—————
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`Withheld ‘TrackNumber: ChemistryQ
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Rajiv Agarwal
`1/19/2007 09:02:37 AM
`CHEMIST
`
`Moo—Jhong Rhee
`1/19/2007 11:45:43 AM
`CHEMIST
`
`Chief, Branch 111
`
`

`

`Initial Quality. Assessment
`Branch III
`
`Pre—Marketing Assessment Division II
`
`0ND Division: Division of Reproductive and Urologic Products
`NDA:
`22-030
`
`Applicant: Schwarz Biosciences, Inc.
`Stamp Date:
`27-Mar—2006 (04-Apr-2006 posted on EDR)
`PDUFA Date:
`26-Jan-2007
`
`Trademark: None proposed
`Established Name: Fesoterodine fiimarate
`
`Dosage Ferm: Extended-release tablet
`-
`Route of Administration: Oral
`Indication: Overactive Bladder
`
`PAL: Donna F. Christner, Ph.D.
`
`ONDQA Fileability:
`Comments for 74-Day Letter
`
`NO
`
`YES
`x
`x
`
`- Summary and Critical Issues:
`
`A. Summary
`
`The drug product is an extended—release tablet. The sponsor refers to it as sustained release
`throughout the package, but is aware that the correct terminology for the US market is extended-
`release and the packaging is labeled to reflect this. The tablets are blue film-coated tablets with
`an engravure on one side. The 4 mg tablet is light blue, while the 8 mg tablet is blue. Tablets are
`packaged in HDPE bottles (30 or 90 tablets) for the commercial presentation and in Al-Al blisters
`for the physicians sample.
`
`Fesoterodine furnarate is a new molecular entity which is a white to off-white powder, freely
`soluble in aqueous solvents, soluble in polar organic solvents and practically insoluble in heptane.
`It is the single »(R)—enantiomer. The drug substance ”WWW '
`the diol SPM 7605, which is the major metabdlite. Labeling states that upon use, fesoterodine is
`immediately de-esterified to its active metabolite.
`
`Clinical studies for this NDA have been performed under IND 51,232. The following CMC
`related meetings/correspondences are captured in DFS:
`
`Cements were sent to the sponsor after the 30—day safety review.
`An EOPZ meeting was held on 13-Jul—2004.
`A CMC preNDA meeting was held on 18-Nov-2005.
`A reply to a General Correspondence dated 12—J211-2006 was generated.
`
`

`

`An overview of the application is provided in the ASSESSMENT NOTES at the end of this
`document. DMFs are provided for non-compendial excipients and container closure systems.
`Relevant reviews are outline inthe DMF table.
`
`B. Critical issues for review
`
`The sponsor has identified a number ofsteps in the synthetic pathway that are critical to the
`quality of the drug substance. Controls will need to be analyzed to determine if they are adequate
`to assure drug substance quality.
`
`Because the drug substanceW assurance should
`be provided that the drug substance is adequately protected during shipping.
`
`
`
`has been measured at levels up to M”, which is.’/
`The new synthesis impurity
`the level for qualification (0.15%) as per ICH Q3A. The sponsor has used these batches in Phase
`1—3 trials, but has not performed toxicology studies using these batches. The sponsor states that
`the impurity is qualified because levels are/ the ICH qualification guidelines.
`
`M4}
`
`M4};
`
`Other review issues are provided below in the Cements for the 74-day Letter.
`
`C. Comments for 74-Day‘Letter
`
`' Please comment on what controls are in place to assure that the drug substance is stored at the
`correct temperature range during shipping, and whether the drug substance is tested at the drug
`product manufacturingfacility prior to use to assure that degradation due to moisture and ~
`temperature sensitivity has not occurred.
`
`N. as stated in the General
`Please confirm that the engravurefor your tablets is
`Correspondence dated 12-Jan-2006. Ifthis is not correct, provide the correct information.
`Please comment on whether the clinical trial supplies had the same engravure.
`
`336%
`
`An additional time point should be added to the dissolution specifications between the 4 hour and
`I 6 hour draws. We recommend a draw at either 8 or 10 hours. Please submit a proposal.
`
`Please be aware that ifa decision is made to package drug product in blisters for commercial
`distribution, the blister packs would need to comply with J 6 CFR 1 700.1 4(a)(1 0) for child
`resistance.
`'
`
`Please submit additional stability data as soon as it becomes available in order to determine
`expiry.
`'
`
`Please submit a tradename to allow complete review ofthe labeling.
`
`D. Recommendation:
`
`This NDA was fileable from a CMC perspective on 11-May-2006. Preliminary comments were
`included for the 74-day letter. A single reviewer, Rajiv Agarwal, has been assigned and will
`evaluate the application to request any additional information deemed necessary.
`
`

`

`On 15-May-2006, the sponsor informed the Division via email that the drug substance V
`manufacturing site would not be available for inspection until after the PAI readiness date of
`September 2006. The sponsor states thatW
`~———'/\ M—--——--—-—-——-‘—"It was not known if the
`
`changes would affect the scale of the drug substance manufacturing process and if the synthetic
`pathway and the resulting impurities would be the same as those submitted originally in the NDA.
`Because a site should be ready for inspection upon submission of the NDA, and because there is
`no data to indicate what the changes are, this change of events was brought to the attention of Dr.
`Elaine Morefield, ONDQA, DPMA H Division Director, and Dr. Moo-Jhong Rhee, ONDQA,
`DPMA 11 Branch III Branch Chief. Dr. Morefield and Dr. Rhee determined that this may be a
`refuse-to-file decision for CMC.
`
`A tcon was held on 16-May—2006 with the sponsor. The sponsor stated during the tcon that the
`change in the manufacturing siteW
`m This 7' 2...“ would make the site not ready
`for inspection until late December 2006, and the sponsor suggested the inspection be scheduled in
`January 2007 (the PDUFA date is 27-Jan—2006). On 17-May-2006, the sponsor sent a General
`Correspondence outlining the changes, stating the site changes would be finished during the
`fourth quarter of 2006, and that the site could‘be inspected sometime within that time period.
`This information was sent to the Office of Compliance (see ASSESSMENT NOTES for email
`string). Office of Compliance stated that the EES would still be pending if no inspection could be
`held. With this information, Dr. Rhee recommended a RTF decision.
`
`On 23-May~2006, John Dietrick, DFI Team Leader, stated that a withhold recommendation could
`be made if the site was not ready for inspection (see second email string), allowing the Division
`to take an action on the PDUFA date. Therefore, this NDA can be filed from an ONDQA
`perspective.
`
`Although the timeline for the review will be decided upon at the Filing meeting, under the GRMP
`guidances, which are being closely adhered to by the clinical division, the review will need to be
`completed by November 2006. The PDUFA date is 27-Jan-2007.
`
`Donna F._ Christner, Ph.D.
`
`

`

`3!
`
`Page(s) Withheld
`
`X Trade Secret ,/ Confidential (b4)
`
`Draft Labeling (b4)
`
`I Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`_
`
`x
`
`Withheld Track Number: Chemistry-_ é
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Donna Christner
`5/24/2006 11:35:07 AM
`CHEMIST
`
`~Moo—Jhong Rhee
`5/24/2006 12:00:30 PM
`CHEMIST
`Chief, Branch III
`
`