CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`'NDA 22-249
`
`CHEMISTRY REVIEW! S!
`
`

`

`NDA 22-249
`
`TREANDA®
`
`Date: March 19, 2008
`
`Introduction
`
`. ONDQA Division Director’s Memo
`
`——
`
`TREANDA® (bendamustine HCl) for Injection is a synthetic new molecular entity
`alkylating agent. It is supplied as a lyophilized p0wder containing the drug substance
`(100 mg) and mannitol (170 mg) in 20 mL amber glass vials. At the time of use, the
`powder is reconstituted with 20 mL Sterile Water for Injection USP to yield a solution of
`5 mg/mL bendamustine HCl. This solution is further diluted with normal saline to a
`concentration of 0.2 to 0.6 mg/mL and administered by IV infusion over 30 minutes.
`
`ONDQA recommends approval.
`
`Administrative
`
`The corresponding IND for this application is 67,554. The NDA was received l9-SEP-
`2007 Was assigned a priority review status (IF) and was part of the GRMP pilot program
`for Oncology Drug Products. The CMC review was complete as of Feb 27, 2008. At
`that time, the Environmental Assessment (categorical exclusion justified) and
`Microbiology reviews (approval recommended) were complete.
`
`However, as per GRMP’s the CMC review was completed on the aforementioned date
`with items NOT under ONDQA control left pending (e.g., EES recommendation). The .
`final recommendation from CC regarding the acceptability of facilities was received 17—
`MAR—2008 (acceptable overall).
`
`Drug Substance and Drug Product
`
`Bendamustine hydrochloride is a new molecular entity synthetic alkylating agent
`(nitrogen mustard type). Being a weak base, the solubility in aqueous solvents is pH
`dependent; being more soluble in acidic media. The drug substance is photosensitive;
`thus the drug substance is packaged and labeled to be protected from light ( “— J
`
`The drug product is a single strength as 100 mg bendamustine HCl plus 170 mg
`Mannitol, in 20 mL amber glass vials sealed with a rubber stopper topped with a crimped
`flip-Offseal. The powder-filled vials are packaged in cardboard containers with the
`notation to “protect from light” on the side panel of the carton and the notation to “retain
`in carton until time of use” on the front panel of the carton.
`
`. At the time of use, the drug product is reconstituted with with 20 mL Sterile Water for
`Injection USP to yield a solution of 5 mg/mL bendamustine HCl This solution which is
`not to be administered may be clear to pale yellow in color.
`
`

`

`This is further diluted with normal saline to a concentration of 0.2 to 0.6 mg/mL and
`administered by IV infusion over 30 minutes. The shelf life of the solution to be infused
`is three (3) hours at room temperature (including infusion time) or twenty four (24) hours
`when at 5C.
`
`The lyophilized drug product is stable for 24 months when stored between two (2) and 25
`degrees C.
`
`Phase—4 Commitment
`
`The applicant agrees to provide assay and impurity profile data within six (6)
`months of approval to assess the compatibility and stability of the infusion solution
`when constituted with other common diluents such as _ L—
`
`Rik Lostritto, Ph.D., Director
`
`ONDQA, Division-III
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Richard Lostritto
`
`3/19/2008 04:47:27 PM,
`CHEMIST
`
`

`

`CMC Branch Chief Memo -
`
`Application: NDA 22-249. Treanda (Bendamustine Hydrochloride) for Injection
`Submission type: 505 (b) (1), Type I (NME)
`Applicant: Cephalon, Inc., 41 Mobres Road, Frazer, PA 19355
`Initial Quality Assessment: Sarah Pope, PhD. (IQA in DFS dated 10/10/2007)
`Primary CMC reviewer: Ravindra Kasliwal, PhD. (Review in DFS dated 2/27/2008)
`
`Overall recommendation:
`
`' All pending issues subsequent‘to cempletion of the primary CMC review have been
`resolved satisfactorily. The Office ofCompliance made an acceptable cGMP
`recommendation for the NDA on March. 17, 2008. The DDMAC and DMETs reviews on
`' labels and labeling were completed and the combined CMC/DMETs comments on labels
`"and labeling were-satisfactorily addressed by the firm. An approval recommendation is
`made for this NDA. A statement on grantable expiration dating period and reminders on a
`CMCpost~marketing-commitment and a CMC agreement, (listed at the end ofthis memo,
`haVe- been included in the action letter.
`
`Background:
`
`The NDA was reviewed under priority clock (6 months) and was the firstGRMP pilot in
`the Division of Drug Oncology Products. The PDUFA date is March 20, 2008.
`
`Introduction:
`
`Bendamustine HCl is 'a nonesterile; synthetic alkylating agent containing nitrogen
`mus'tardstructural element and has known genotoxic nature. Chemically, it is lH-
`Ben'zimidazole-Z-butanoic acid, 5_-[bis(2-chloro.ethyl) amino]-l-methyl-,
`,
`.
`_
`monohydrochloride. The USAN and INN name for the drug substance is bendamustine
`.
`hydrochlorideThe primary CMC review indicated that the long-tenn drug substance
`stability data support the proposed
`’— retest period when stored at 2°-25°C (36°-
`77°F) and protected from light (bendamustine HCl is photosensitive).
`
`-,
`
`_
`
`(z:
`
`5.
`
`on,
`CIGHZICIJNJOZ
`Mol. WL: 394.7
`C 4869211. 5‘62: CL 16.91: N. [0552 0‘ 3.“
`
`The TREANDA® (bendamustine HCl) for Injection is packaged as a lyophilized powder,
`in 20-cc amber glass vials in 100 mg strength. Each 100 mg vial is to be reconstituted
`
`NDA 22-249
`
`Branch Chief Memo
`
`lof 36
`
`

`

`with-20 mL of Sterile Water for Injection (WFI), to yield a 5 mg/mL bendamustine HCl
`solution. This solution is to be further diluted-to a concentration of 0.2 to 0.6 mg/mL with
`0.9% Sodium Chloride Injection, USP (NS, normal saline). The product dose is
`determined based on patient body surface area. The drug product is diluted into 500 mL
`IV normal saline bags, thus yielding the abbve drug concentrations Administration is
`performed by [V infiision over the recommended 30 minute infusion time. The
`paperboard folding carton is used to package the vial and15 also intended to provide
`protection from light as bendamustine HCl drug substanceis photosensitive (degrades
`upon exposure to light). The primary CMC review indicates that adequate data are
`provided to support the requested expiration datingperiod of 24 month when stored at 2°-
`25°C (36°-77°F) and retained in the original package to protect from light. The product is
`required to have the statement “Protect from light” on the label.
`
`Pending CMC-related issues from the p'rimgy CMC review:
`
`At the time the primary CMC review Was placedin DFS,the followingissues were still
`pendingresolution andor feedback.
`~
`
`1
`2.,
`3
`
`4. '
`
`OSE/DMETS review of labels and labeling ‘
`OVerall recommendatibn from the Office of COmpliance
`CMC post-marketingcommitment to include additional studies on
`comnatibilitv ofthe drug product with diluents such as l ——\.
`___’___/_,____.
`
`' Firm’s agreement dated 12-Feb-2008 to'initiate change controls for all the
`documents impacted byrthe revision to the maximum hold time not to exceed
`m C and to submit
`
`appropriate post-apprOval correspondence reflecting this change
`
`The memo'serves to address these pending issues andto close out the CMC review
`and to provide an overall approval recommendation for this NDA.
`
`OSE/DMETs and DDMAC. review cflabels and labeling.':
`
`The DDMAC/SE'ALD review bv Iris Masucci was placed in BPS on February 19.
`2008. She recommended e—e—R
`
`_
`
`///
`
`NDA 22-249
`
`Branch Chief Memo
`
`20f 36
`
`

`

`“LPag€<S> ithheld 5 -
`
`.
`
`.
`
` Trade 'S-ecref/ -CQHfid€_flt_ial
`/DraftLabeling ‘
`._
`~
`
`
`
`' . A
`
`'_
`
`V
`
`‘ H
`
`_ _
`
`
`
`.
`
`:DE‘lib-‘eratwePTOCQSS
`
`'
`
`

`

`The updated package insert was submitted by the firm on March 17, 2008. This was
`reviewed by the team during the last labeling meeting on March 18, 2008 and was ,
`~
`deemed acceptable with some revisions. The final version of the PI is attached
`(Attachment 3).
`
`Overall recommendation from the Office of Compliance:
`
`NDA 22-249
`
`Branch Chief Memo
`
`40f36
`
`

`

`was
`
`On March 17, 2008,.the Office of Compliance provided an overall acceptable
`
`recommendation for this NBA. The detailed e-mail'correspondence is attached
`(Attachment 1). It can be noted that the: M ~ site,
`withdrawn from the EES request since this site is only responsible for ___/-
`V‘whereas the actual analysis18 carried out in the respective
`manufacturing sites, which are already deemed acceptable. The facility inspection
`report is attached (Attachment 2). During the initial qualityassessment, the
`pharmaceutical assessment lead entered the sites in} EES and indicated that '
`was the ~—’
`site (profile code CTL); However. during'the review it was
`uncovered that this site onlyM
`’
`was carried out at the drug substance manufacturing site. In retrospect,
`this site should not have been requested for1nspection This was made clear to me by
`Edvin Rivera-Martinez. He indicated during a telephone discussion on 3/ l7/08 that
`sites such as this, which are meant to E s, are not routinely
`inspected unless there is a reason to do so. Therefore, upon discussion with him and
`as per his recommendation, we withdrew this site from inspection in the BER on
`3/ 17/08.
`
`CMC-Post-marketing Commitment and-agr' cement:
`The following PMC was agreed to between the Agency and the firm on March 3,
`2008. The firm submitted an amendment
`Study title:
`Assessment ofphysicojchemiml compatibility ofTreanda with the
`following diluents as admixtures to reconstituted TREANDA:M
`———~_.
`sodium chloride)
`'Protocol submission Aprill, 2008 _
`Studytmtianon May 15, 2008
`Study report submission: September 1,2008
`
`Rationale and Background: Treanda admixutre studies were conducted during
`development using normal saline as theproposed diluent. The study willcontinue by
`performing compatibility of the admixture at the end of the proposed shelf life, which is
`24 months. Additional commonly used diluents will be added to the end of shelf life
`
`study to generate data for- alternative diluents. M’
`
`. Each diluent will be studied over the storage time and
`temperature in the proposed label.
`
`This commitment was included in the action letter. Similarly, a reminder to‘the firm,
`about their agreement to initiate change controls to update the hold times was also
`included in the action letter.
`
`NDA 22-249
`
`Branch Chief Memo
`
`"
`
`50f 36
`
`

`

`Attachment 1: E—mail correspondence with the Office of Compliance
`From:
`CDER EESQUESTIONS
`Sent:
`Monday, March 17, 2008 4:18 PM
`To:
`Harapanhalli Ravi S; Rivera Martinez, Edwin
`Cc:
`Lostritto, RichardT; Justice, Robert; Ibrahim, Amna; Pope, Sarah; Dagher
`Ramzi; Cross Jr, FrankH; Kasliwal, Ravindra K; Nasr Moheb M; Friedman
`Rick L; Jones, Carole (OC/DMPQ), Cruz, Concenm'nn
`RE: NDA 22-249:Treanda. Inspection status of: N
`
`Subject:
`
`_
`
`An acceptable overall has been entered into EES.
`Shirnette
`
`From:
`Sent:
`To:
`Cc:
`
`Harapanh'alli, Ravi 5
`Monday, March 17,2008 _1:38 PM
`CDER EESQUE-SHONS; Rivera Martinez, Edwin
`Lostrittio, Richard T, Justice, Robert; Ibrahim, Amna; Pope, Sarah; Dagher, Ramzi; cross Jr, Frank H;
`Kasliwal, Ravindra K; Nasr, Moheb M, Friedman, Rick L; Harapanhalli, Ravi S; Jones, Carole
`(OC/DMPQ); Cruz, Concepcion
`RE: NDA 22-249: TreandaInspection status of E
`Subject:
`Importance: High
`'
`'
`
`Edwin,
`
`Thanks for the r‘all and for discussing the'pending inspection-Ewewith this NDA. As we
`discussed the \- site has been withdrawn from the EES request. This should pave
`the way for an overall 00 recommendation.
`
`When the sites were entered into the EES during the initial quality assessment (IQA) phase
`of the NDA review, based on the limited information, this .site was entered as a stability
`testing site with a CTL profile code. However, duringsubsequent in—depth review, we
`uncovered, this site M and does not carry outany stability testing.
`By that time since the inspections had been scheduled, we Communicated with you via the
`EES Questions email account
`
`Glad that we could resolve. thisIssue quickly
`Looking forward to an overall compliance recommendation before March 20,2008
`
`Row 3. Haroponhalli, PhD.
`Chief; Branch V (CMC-Pre-marketing)
`Division of Pre—market Assessment and Manufacturing Science
`Office of New Drug Quality Assessment (ONDQA) CDER, FDA,
`Bldg. 22, Room #24l4
`[0903 New Hampshire Avenue.
`Silver Spring, MD 20993-0002 ,
`Phone: 30I 796 1676; Fax: am 796 9850
`
`
`
`From:
`Harapanhalli, Ravi 8'
`Sent:
`Friday, March 14,2008 4: 06 PM
`To:
`~
`Jones, Carole (OC/DMPQ); Cruz, Concepcion; CDER EESQUESTIQNS
`Cc:
`Lostritto, Richard T; Justice, Robert; Ibrahim, Amna; Pope, Sarah; Dagher, Ramzi; Cross Jr, Frank H;
`Kasliwal, Ravindra K, Nasr, Moheb M; Rivera Martinez, Edwin; Friedman, Rick L
`Subject: RE: NBA 22—249: Treanda. Inspection status of “1-“
`Importance:
`High
`
`Your e—mail indicates that the facility. m cannot
`
`NBA 2449
`
`'
`
`Branch Chief Memo
`
`.
`
`6of36
`
`

`

`,
`
`be inspected until after the PDUFA date. However, as indicated earlier the NDAIs being
`recommended for approval from all the disciplines and the Medical DivisionIs looking
`forward to the action and to meet the PDUFA goal date whichIs March 20, 2008 Also
`pending the ._. site, all- other facilities have been deemed acceptable for cGMPs.
`
`it appears that there is a case for regulatory discretion to waive the inspection of
`and to approve the NDA The facility may then be inspected following the approval of the
`NDA, as scheduled on April 7-8 2008. Here are the reasons.
`
`1.
`
`5—" ; is the facilitv fnr —-~——————-—-————_.
`
`,
`
`mW
`
`.. This facility does not analyze the stability samples.
`
`The stability samples are analyzed by the respective drug substance and the
`2.
`drug product manufacturingsites, which have already been inspected and deemed
`acceptable for cGMP compliance.
`
`Analysis of primary and stipporting. stability data provided'In the NDA indicates
`3.
`that the drug substance and the drug product arestable over a wide temperature range
`from 2 C to 40 C There wereno significant changes on accelerated storage at4OC/75%. ._';
`RH over
`-—-
`Therefore itIs a very stable drug
`Understandably, —-— is a new facility.and has neverbeeninspected..However
`given that the productIs stabie over a wide range of temperatures and any temperature
`fluctuationsIn the stability chambers may not significantly affect the product quality, we
`recommend a risk based approachIn the regulatory discretion to provide an overall
`recommendation now and to conduct the inspection of this facility as scheduled. This will
`assure that the PDUFA date can be met for this priority NDA whichwas reviewed under
`GRMP pilot program.
`
`If you have any questions. please let us know.
`
`Row 5. Horoponholll, Ph.D.
`Chief. Branch V (CMC-Pre-marketing)
`Division ofPre1market Assessment and Manufacturing Science
`Office of New Dmg Quality Assessment (ONDQA), CDEK FDA.
`Bldg. 22, Room tt 2414
`10903 New Hampshire Avenue,
`Silver Spring, MD 20993-0002
`Phone: 30l 796 I676; Fax: 301 796 9850
`
`
`
`Jones, Carole (OC/DMPQ)
`From:
`Wednesday, March 12, 2008 4.02 PM
`Sent:
`To: Harapanhalli, Ravi S; Cross Jr, Frank H, Kasliwal, Ravindra K, Cruz, Concepcion
`Cc: Lostritto, Richard T, Justice, Robert; Ibrahim, Amna; Pope, Sa_;rah Dagher, Ramzi
`Subject:
`RE2 NDA 22--2249 Tr‘eanda. Inspection status of f“
`
`Unfortunately, the inspection could not be planned prior to the PDUFA date. It is
`schedule to: ” Since this is a new facility with no previous GMP history, we
`cannot provide a GMP assessment of this facility at this time.
`
`Thanks,
`_ Carole Jones
`Acting Team Leader
`
`NDA 22-249
`
`Branch Chief Memo
`
`‘
`
`70f 36
`
`

`

`international Compliance Team
`301-796—3194
`
`From: Harapanhalli, RaVi S
`Sent: Wednesday, March 12, 2008 3:56 PM
`To: Cross Jr, Frank H; Kasliwal, Ravindra K; Jones, Carole (OC/DMPQ); Cruz,
`Concepcion
`Cc: Lostritto, Richard T, Justice, Robert, Ibrahim, Arnna; Pope, Sarah; Dagher,
`Ramzi
`Subject: RE: NDA 22—249: Treanda. Inspection status of’ :3:-
`
`Let us wait to hear back from 00:
`
`Raw 3. HaropanhailI, PhD.
`Chief, Branch V (CMCsPIIe-onarketing)
`Division of Pre—market Assess'ment and Manufacturing Science
`Office of New Drug Quality Assessment
`(0NDQA),
`ICDER, FDA,
`Bldg. 22, Room # 2414
`.
`‘
`10903 New Hampshire Avenue,
`Silver Spring, .MD 20993—0002
`Phone: 301 796'1676;~_Fax: 301 796 9850 I
`
`From:
`.Sent:
`To:
`
`'
`Cc:
`Subject:
`So we are
`
`.
`
`Cross Jr, Frank H
`Wednesday, March 12, 2008 3:55 PM
`Kasliwal, Ravindra K, Harapanhalli, Ravi S; Jones, Carole (OC/DMPQ); Cruz,
`Concepcion
`Lostritto, Richard T; Justice, Robert; Ibrahim, Arrina; Pope, Sarah; Dagher, Ramzi
`w
`RE. NDA 22-249: Treanda Inspection statusof
`
`going to miss the PDUFA Date.
`
`Frank
`
`From:
`Sent:
`To:
`
`Cc:
`Subject:
`
`Frank,
`
`Kasliwal, Ravindra K
`Wednesday, March 12,2008 3:51PM
`Cro'ss Jr, Frank H; Harapanhalli, Ravi S; Jones, Carole (OC/DMPQ); Cruz,
`Concepcion
`Lostritto, Richard T; Justice, Robert; Ibrahim, Amna; Pope, Sarah
`RE: NDA 22-249: Treanda. Inspection status at
`.—=—-
`
`This is the only site and there is no alternate site for the task \ l. So the
`site is required for approval. Obviously they could not find the profile.
`
`Ravi Kasliwal
`
`From:
`Sent:
`
`Cross Jr, Frank H
`Wednesday, March 12, 2008 3:38 PM
`
`NDA 22-249
`
`Branch Chief Memo
`
`80f 36
`
`

`

`To:
`Cc:
`'
`
`Harapanhalll,Ravi S; Jones, Carole (OC/DMPQ); Cruz, Concepcion
`Lostritto, Richard T; Justice, Robert; Ibrahim, Amna; Kasliwal, Ravindia K; Pope,
`Sarah
`
`Subject:
`
`RE: NlDA 22—249: Treanda. Inspection status of
`
`——-—'
`
`Is this site required for approval?
`
`If so, can this be a. profile.
`
`Thanks,
`Frank
`
`From:
`Sent:
`To:
`Cc:
`Subject:
`Importance:
`
`Harapanhalli, Ravi S
`Wednesday, March 12, 2008 3:32 PM
`'
`Jones, Carole (OC/DMPQ); sz,.Concepcion
`Harapanhalli, Ravi S, Lostritto, RichardT; Cr.oss Jr, Frank H, Justice, Ruben;
`lbrahim,'A'mna;_ Kasliwal, Ravindra K; Pope, Sarah
`'
`RE: NBA 22—249: Treanda. Inspection status of
`\—
`__ High
`:
`
`Please note that the PDUFA date is March 120, 2008 (not, March '30'as indicated
`in your e-mail below\ and the Division intends to take an early action‘ifpossible.
`If the inspection of
`. is scheduled on _"'
`'we won't. be able to meet
`the PDUFA da‘te.
`
`Rows. Haraponhalli, Ph. D.
`Chief, Branch V (CMC- Pre—marketing)
`Division of Ere—market Assessment and ManufacturingScience
`Office of New Drug Quality Assessment
`(ONDQA), CDER, FDA,
`Bldg 22, Room it 2414
`10903 New Hampshire Avenue,
`Silver Spring, MD 20993-0002
`Phone: 301 796 1676,- Fax: 301 796 9850
`
`
`'
`From:
`Jones, Carole (OC/DMPQ)
`Sent:
`Wednesday, March 12,2008 2:37 PM
`To:
`Cruz, Concepcion; Harapanhalli. Ravi 5
`Subject:
`FW: Inspection status of p—fi
`
`Please see Irma's e—mall below for the inspection date of __/
`
`Thanks,
`Carole Jones
`Compliance Officer
`FDA/CDER/OC/DMPQ
`International Compliance Team
`301-796-3194
`
`
`
`From:
`
`Rivera, Inna
`
`NDA 22-249
`
`Branch Chief Memo
`
`9of‘36
`
`

`

`Sent:
`To:
`Subject:
`
`Tuesday, March 04, 2008 9:02 AM,
`Had<ett, Rebeca R; Adams. Shawnte L
`RE: Inspection status of f
`—/
`
`This inspection is scheduled for
`
`From: Adams, Shawnte L
`Sent: Tuesday, February 26, 2008 10:51 AM
`To: Hackett, Rebecca R
`.
`Subject: Inspection status of A
`
`Becky, .
`
`V
`
`.
`
`Please prOvide the status of the inspection scheduling of ~
`~————\———
`This facility is listed in
`NBA 22249 which hasa PDUFA date :of March 30, 2008.
`
`Thank'you,
`
`ShawnteL. Adams
`Program Analyst
`Office of Compliance
`DiviSion ofManufacturing and Product Quality
`lntemational COmpliance Team
`'
`'
`301-796-3193 (Office)
`General Foreign Inspection questions should be directed to:
`cderict@fda.hhs gov
`FWAP: Tuesday and Thursday
`
`I
`
`NDA 22-249
`
`Branch Chief Memo
`
`'
`
`100f36
`
`

`

`Attachment 2: Facility Inspection Report
`18—MA-2008 FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`
`‘
`
`Page I of 2
`
`SUMMAY REPORT
`
`Application NDA 22249/000 Sponsor: CEPHALON INC
`Org Code150 NO CITY, , XX
`Priority 1P
`
`-
`Stamp Date 20-SEPL2007 Estab. Name:
`PDUFA Date 20—MA-2008 Generic Name: BENDAMUSTINE HCL
`
`Brand Name : TREANDA
`
`'
`
`Action Goal Dosage Form: (INJECTION)
`District Goal: 20 JAN-2008 Strength 100 MGNIAL
`
`FDA Contacts:
`
`.V
`
`._
`K. STILLER
`R. KASLIWAL Review Chemist
`R. HARAPANHALLI Team Leader
`
`Project Manager ~(HFD—580) 301796 1993
`‘
`f
`
`301-796—1386
`301-796-1676
`
`Overall Recommendation: ACCEPTABLE on 17 MAR-2008 by C. CRUZ (HFD-
`323) 301-796-3254
`'
`-
`
`,
`Establishment:
`
`.__= .
`CFN: 4— FEI:
`
`M
`
`. DMF No:
`
`'
`
`.
`
`AAA:
`
`Responsibilities:
`
`CSN OAI Status: NONE
`.
`Profile
`Last Milestone: OC RECOMMENDATION
`' Milestone Date: 26-FEB-08
`' Decision ACCEPTABLE
`Reason DISTRICT RECOMMENDATION
`
`‘
`
`Establishment:
`
`CFN \" FEI \
`
`. N
`
`NDA 22-249
`
`Branch Chief- Memo
`
`l [of 36
`
`

`

`DMF No: N
`
`Responsibilities:
`
`/J'/
`/
`
`SVL OAI Status: NONE
`Profile
`Last Milestone: OC RECOMMENDATION
`Milestone Date: 27—NOV-07
`Decision ACCEPTABLE
`Reason DISTRICT RECOMMENDATION
`
`Establishment:
`
`CFN' ——‘-
`
`FEI'
`
`’—
`
`-lS-MA-ZOOS
`
`DMF No:
`
`Responsibilities: Profile
`
`Last Milestone:
`Milestone Date:
`
`Decision
`
`' Reason
`
`Establishment :
`
`DMF No:
`
`Responsibilities: Profile
`
`Decision
`Reason
`
`Last Milestone:
`Milestone Date:
`
`NDA 22-249
`
`Branch Chief Memo
`
`120f 36
`
`

`

`FDA CDER EES ESTABLISHMENT EVALUATION
`REQUEST SUMMAY REPORT AAA:
`
`Page 2 of2
`
`/
`
`/
`
`SVL 0c RECOMMENDATION 15-
`mm ACCEPTABLE DISTRICT
`RECOhflMENDAflION
`
`OAI Status:
`
`NONE
`
`CFNV "'
`/ /
`/
`I
`
`FEI: ”a
`
`NONE
`
`M O
`
`AI Status:
`
`SVL 0C RECOMMENDATION
`.01-0CF-07 ACCEPTABLE BASED
`
`ON PROFILE
`
`NDA 22-249
`
`'
`
`Branch Chief Memo
`
`l3of 36
`
`

`

`Attachment 3: Final package insert dated 3/ 18/2008: (This is the revised version based on the labeling
`meeting at 2:30 PM on 3/18/08)
`'
`
`- PPPEARS THIS WAY
`0N ORIGINAL
`
`NDA 22-249
`
`Branch Chief Memo
`
`__
`
`Mat" 36
`
`

`

`
`
` /
`
`
`
` Dr‘aflLabeliIig -
`
` DehberatweProcess
`
`'
`
`

`

`4 " Label Code:
`(5
`.
`
`[440014-00
`
`APPEARS nus WAY .
`on ORIGINAL
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`March 14 2008 Ceph Version
`33'
`
`P??? EARS MES WAY
`Mg MMQWM
`
`

`

`APPMRS THES WAY
`0N ORiGBNAL
`
`APPEARS mm mm
`' on omemm
`
`March 14 2008 Ceph Version
`34
`
`

`

`APPEARS THIS WAY
`ON QRRGWM
`
`MPEARS was WAY
`0N ORIGINAL
`
`March 14 2008 Ceph Version
`35
`
`APPEARS was way-
`0N ORIGINAL
`
`

`

`CMC comments and reminders to be included in the action letter:
`
`1'.
`
`An expiration dating period on4 months is granted when stored as
`recommended in the approved product labeling. You may extend the
`expiration dating based on accrual of real-time-stability data and report this in
`an‘annual report for this NDA.
`_
`Cephalon commits to assess the physico«chemical compatibility of Treanda
`with the following diluents as admixtures toreconstituted TREANDA: --’
`W :‘odium chloride).
`'
`
`Protocol submission: April 1,2008
`Study start: May 15, 2008
`Final R:eport September 1, 2008
`We also remind you ofyour agreement dated 12-Feb-2008 to initiate change
`controls for all the documents impacted by the revision to the maximum hold
`time not toexceedM and
`- to submit appropriate post-apprOVal correspondence reflecting this change1n
`thenext annual report.
`
`”Mad
`
`March [4 2008 Ceph Version
`36
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Raiii Harapanhalli
`3/19/2008 09:49:56 AM
`CHEMIST
`.‘
`AP recommendation
`
`'Richard Lostritto
`3/19/2008 11;16:59 AM
`CHEMIST '
`~
`'
`
`

`

`18<MAR—2008
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Page 1 of 2
`
`Application
`Org Code
`Priority
`
`NDA 22249/000
`150
`
`: 1P
`
`Stamp Date
`PDUFA Date
`.
`Action Goal
`District Goal:
`
`20-SEP-2007
`20-MAR—2008
`
`20—JAN—2008
`
`Sponsor:
`
`CEPHALON INC
`NO CITY,
`, XX
`
`Brand Name
`_ Estab. Name:
`Generic Name:
`Dosage Form:
`Strength
`
`TREANDA
`
`BENDAMUSTINE HCL
`(INJECTION)
`100 MG/VIAL
`
`FDA Contacts:
`
`K. STILLER
`R. KASLIWAL
`R. HARAPANHALLI
`
`Project Manager (HFD~580)
`Review Chemist
`Team Leader
`
`301-796-1993
`301—796-1386
`301—796<1676
`
`'
`
`DMF NO:
`
`Responsibilities:
`
`AADA:
`
`.
`Profile
`Last Milestone:
`Milestone Date:
`Decision
`Reason
`
`CSN‘
`OC RECOMMENDATION
`26-FEB~08
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`OAI Status:
`
`NONE
`
`DMF NO:
`
`AADA:
`
`Responsibilities:
`
`.
`Profile
`Last Milestone:
`Milestone Date:
`Decision
`Reason
`
`Establishment
`
`.
`
`/
`
`/
`
`OC RECOMMENDATION
`27—Nov—07
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`OAI Status:
`
`NONE
`
`“HM—.—__......_.....
`
`

`

`lB—MAR-ZOOS
`
`DMF NO:
`
`FDA CDER EES '
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`AADA:
`
`Page 2 of'2
`
`Responsibilities:
`
`
`
`.
`Profile
`Last Milestone:
`Milestone Date:
`Decision
`Reason
`
`Establishment
`
`SVL
`
`0C RECOMMENDATION
`15~OCT-07
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`DMF NO:
`
`AADA:
`
`Responsibilities:
`
`.
`Profile
`Last Milestone:
`Milestone Date}
`Decision
`:
`Reason
`
`SVL
`
`0C RECOMMENDATION
`Ol—OCT-07
`ACCEPTABLE
`BASED ON PROFILE
`
`OAI'Status:
`
`NONE
`
`OAI Status:
`
`NONE
`
`

`

`
`
`NDA 22-249
`
`TREANDA®
`
`(bendamustine hydrochloride) for injection
`
`Cephalon, Inc.
`41 Moores, Rd.
`
`Frazer, PA 19355
`
`Ravindra K. Kasliwal, Ph.D.
`
`CMC Reviewer
`
`Division of Pre—marketing Assessment and
`Manufacturing Science,
`Branch V, ONDQA
`
`CDER, FDA
`
`For The Division of Drug Oncology Products
`
`

`

`
`
`Table of Contents
`
`Table of Contents .......................................... ...........................................................2
`
`Chemistry Review Data Sheet................. ...........
`
`...........
`
`........... ...........
`
`........3
`
`The Executive Summary ....... . .................... ...........
`
`.......................................
`
`..... 6
`
`I. Recommendations ...................................................................................................................... 6
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 6
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable ................................................................................................... 6
`
`II. Summary of Chemistry Assessments ......................................................................................... 6
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 6
`
`B. Description of How the Drug Product is Intended to be Used .......................................................... 7
`
`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
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ......... 9
`
`S DRUG SUBSTANCE [Name, Manufacturer] ................................................................................ 9
`
`P DRUG PRODUCT Wame, Dosage form] .................................................................................... 67
`
`A APPENDICES ............................................................................................................................ 107
`
`R REGIONAL INFORMATION ................................................................................................... 107
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ................................ 107»
`
`A. Labeling & Package Insert .......................................................................................................... 108
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................. 1 10
`
`III.
`
`List Of Deficiencies To Be Communicated ..................................................................... 113
`
`

`

`
`
`CHEMISTRY REVIEW "
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 22—249
`
`MANN
`
`. REVIEW #2 1
`
`. REVIEW DATE: l9-Feb—2008 (revised 27-Feb—2008)
`
`. REVIEWER: Ravindra K. Kasliwal, Ph.D.
`
`. PREVIOUS DOCUMENTS: None
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission( 5) Reviewed
`Original
`Amendment (BC)
`Amendment (BC)
`Amendment (BC)
`Amendment (BC)
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`l9-Sep—2007
`17-Dec-2007
`12-Feb-2008
`14-Feb-2008-
`22-Feb—2008
`
`Name:
`
`Address:
`
`Cephalon, Inc.
`
`41 Moores Road, PO. Box 4011, Frazer, PA 19355
`
`Re resentative'
`p
`'
`
`Carol S. Marchione, Sr. Director and Group Leader,
`Regulatory Affairs
`
`Telephone:
`
`(610) 73 8-6237
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Treanda®
`b) Non—Proprietary Name: Bendamustine hydrochloride (USAN & INN)
`0) Code Name/# (ONDC only): CEP-18083, BMl, SDX-105, ID08736, M008736, ID00275,
`M000275, ID00039, M000039, IMET 3393, ZIMET 3393
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 1
`
`0 Submission Priority: P
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b) 1 application.
`
`Page 3 of113
`
`

`

`
`
`” CHEMISTRY REVIEW ~
`
`,
`
`10. PHARMACOL. CATEGORY: Alkylating Agent
`
`Chemistry Review Data Sheet
`
`11. DOSAGE FORM:
`
`Lyophilized powder for injection
`
`12. STRENGTH/POTENCY:
`
`100 mg/vial
`
`13. ROUTE OF ADMINISTRATION: intravenous
`
`14. RX/OTC DISPENSED:
`
`_X_Rx
`
`OTC
`
`
`15.8SPOTS (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: 1H-Benzimidazole-Z-butanoic acid, 5-[bis (2-chloroethyl) amino]-1-methyl-, monohydrochloride
`Cl
`
`8W
`
`OW
`
`\CH3
`C16H12C'3N302
`M0]. Wt: 394.7
`C, 48.69; H, 5.62; Cl, 2694; N, 10.65; 0, 3,1]
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
` DATE REVIEW
`STATUS2
`CODE]
`HOLDER flTEM/REFERENCED
`’iM/F# ‘ TYPE
`COMPLETED COMMENTS
`
`
`‘III
`
` Ph.D i/ i111 / / 3,4 Adequate
`
`
`
`
`3, 4
`Adequate
`22-Apr-2002 by
`None
`Yvonne Yang,
`Chikale
`
`
`
`10-Oct-2002 by
`Dr. Elsbeth
`
`None
`
`'
`
`./
`
`1 Action codes for DMF Table:
`l — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`
`Page 4 ofll3
`
`

`

`
`
`Chemistry Review Data Sheet
`
`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:
`
`
`DOCUMENT
`APPLICATION NUMBER
`DESCRIPTION
`
`Ce halon IND for bendamustine HCl
`IND 67, 554
`
`N/A
`
`18. STATUS:
`
` ONDC:
`CONSULTS/ CMC
`-
`
`REVIEWER
`DATE
`RECOMMENDATION
`RELATED
`REVIEWS
`
`
`Biometrics
`N/A
`Acceptable
` EES
`Pharm/Tox
`N/A
`
`
`Bio harm
`N/A
`
`LNC
`N/A
`
`
`
`
`Methods Validation
`
`Analytical methods are
`conventional; DPA
`verification will not be
`
`wasted.
`
`OSE / DMETS
`PENDING
`Pending
`EA
`Claim for categorical
`Same as the
`Ravindra K. Kasliwal, Ph.D.
`
`exclusion ii'flistified
`review date.
`Microbiology Anastasia G. Lolas Approval 06-Feb—2008
`
`
`
`
`
`Page 5 of113
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`The Chemistry Review for A/NDA 22-249
`
`The Executive Summary
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The application is recommended for an approval action for chemistry, manufacturing and controls under section 505
`ofthe Act, provided trademark and labeling acceptability has been determined by Office of Drug Safety (DMETS)
`and provided the manufacturing sites are deemed acceptable for cGMP compliance. The product quality
`microbiology has recommended approval on 06-Feb-2008. The recommendation for Office of Compliance regarding
`the acceptability of the manufacturing facilities is pending as of the date of this review.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`The company has not provided data showing compatibility of the constitution solution, Sterile Water for Injection,
`
`USP, with other commonly available diluents such as
`,.
`.
`,
`The data (assay and
`impurity profile) should be provided as part of the phase 4 commitment within 6 months of approval of the
`application (comment for company is provided at the end of this review).
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The TREANDA® (bendamustine HCl) for Injection is packaged as a lyophilized powder in 20-cc amber glass vials
`in 100 mg strength. Each 100 mg vial is to be reconstituted with 20 mL of Sterile Water for Injection (WFI), to yield
`a 5 mg/mL bendamustine HCl solution. This solution is to be further diluted to a concentration of 0.2 to 0.6 mg/mL
`with 0.9% Sodium Chloride Injection, USP (NS, normal saline). The product dose is determined based on patient
`body surface area. The drug product is diluted into 500