CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205580Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`Executive Sunny
`
`1.
`
`Recommendations and Conclusion on Approvability
`
`OPQ reconlnends APPROVAL of NDA 205580 for Bendamustine Hydrochloride
`Injection, 100 mg/4 mL (25 mg/mL). As part of this action, OPQ grants a gymonth re-
`test period thr the drug substance when storedin
`Mt"
`
`There are no outstanding Issues and no post-approval
`agreenents to be conveyed to the applicant.
`
`II.
`
`Si-mnry of Quality Assessments
`
`A. Product Overview
`
`Bendanlistine is a s-ll nnlecule alkylating agent that was originally approved by the
`FDA in 2009 (NDA 22249) ibr treahmnt ofpatients with chronic lyirphocytic leukemia
`(CLL) and indolent B—cell non-Hodgkin lynyhorm (NI-IL) tlnt has progressed during or
`within six mmfln of treatrmnt with rituxirmb or antuximab containing regirmn NDA
`205580 was submitted as a 505(b)(2) NDA with Treanda® (bendanlistine) as the Listed
`Drug (LD). The proposed drug product, Bendamistine Hydrochloride Injection, 100
`mg/4 mL (25 mg/mL,
`is a ready-to—dilute solution, whereas the ID is a lyophilized
`powder that requires reconstitution. The drug product ‘8 intended for IV infiniorr
`
`Bendamistine Hydrochloride is nnmrtactured by
`
`M“)
`
`M“)
`(bi(4)_
`
`Infimmtion pertaining to the nmiulacture and control of the drug substance was
`incorporated "1110 the application by way of reierence to DMF
`(m4) DMF
`00(4) was
`reviewed in conjunction with the review of NDA 205580 and was deemad adequate to
`support the approval ofNDA 205580. The drug product, bendanlistine hydrochloride,
`25 mg/mL 's aready—to-dilute,
`“‘4’, self-preserving solution tbrnmlation
`intended lbr multiple doses. The drug product formilation includes 25 mg/mL of
`bendannstine hydrochloride (100 mg/vial), 5 mg/mL of nnnothioglycerol as an
`M" (20 mg/vial), and 0.1 mUmL of propylene glycol as a
`(0.4 mg/v'nl) in polyethylene glycol 400 (QS to 4 mL). The drug product '6
`sterilized by
`(mm
`(hm)
`(him
`
`(hm)
`
`The dosing regimen for Bendanlstine Hydrochloride Injection, 100 mg/4 mL (25
`mg/mL) for patients with chronic lynphocytic leukemia (CLL)IS 100 mg/m admin'ntered
`intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles The dosng
`regimen 1hr Bendamistine Hydrochloride Injection, 100 ng4 mL (25 nig/mL) for
`patients with indolent B—cell non-Hodgldn lynphoma (NHL)is 120 mg/m admin'stered
`intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles
`Based onthe intbmiation provided in this application (origiial submission, resubmsion,
`amendments and respomes to information requests), OPQ considers all review issues
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 1 of 3
`
`Efliective Date: 14 February 2017
`
`Reference ID: 4266336
`
`

`

`QUALITY ASSESSNIENT
`
`adequately addressed and potential risks to patient safety product eflicacy, and product
`quality mitigated appropriately. Accordingly OPQ recommnds APPROVAL ofNDA
`205580 and grants a (4i-month re—-test period for the drug substance and a 24 month
`expiration period for the drug product when stored between 2 -8 C (36 to 46 F)In the
`comrmrcfil packaging The drug product should be used within 24 hours when held
`under refiigeration or 3 hours when stored at room temperature (fliese tines include
`administration tine). Each vial is not recommended for more than a total of six dose
`withdrawals and should be discarded afler 28 days.
`
`Proposed Indication(s) including
`Intended Patient Population
`
`0 Chronic lyrnphocytic leukemia (CLL). Efficacy relative
`to first line therapies other than chlorambucil has not
`been established
`
`Indolent B-cell non-Hodgkin lymphoma (NHL) that has
`progressedduring or within six months of treatment
`with rituximab or a rituximab—containing regimen
`
`Duration of Treatment
`
`Ie recommended dose for CLL is 100 mg/m‘
`.dministered intravenously over 30 minutes on Days 1 and
`I of a 28—day cycle, up to 6 cycles.
`
`ue recommended dose for NHL is 120 mg/m2
`
`dministered intravenously over 60 minutes on Days 1 and Alternative Methods of
`
`Adninistration
`
`None
`
`B. Quality Assessment Overview
`NDA 205580 was originally submitted in February 2013 and tentatively approved (TA)
`in July 2014. The applbation could not be granted final approval until all exchsivities
`expired. There were no outstanding CMC issues at th's tirm. NDA 205580 was
`resubmitted to the agency in January 2018. At which time it was concluded that this
`application would be a Class 1.
`
`By Product:
`there were nnditimtions noted in the proposed drug product
`In the resubmsion,
`specifnations based on approved post-marketing CMC srbmissions tbr BENDEKA
`(bendamustine hydrochloride) injection 100mg/4mL (25 mg/mL) lbr infiision under
`Eagb’s NDA 208194 which was approved in Decenber 2015. Ofnote, the DP
`reviewer states that due to the current OPQ policy on resubmsions for
`implementation of USP<232> and USP<233>, the elemental
`impurities specification in
`the drug product was verified (see appended drug product memo).
`
`the applicant requested a 24 month ermgvmfin the drug
`In the orignal subrm'ssion,
`product. At that firm the drug product reviewer reconnended an
`momh expiry ibr
`the drug product.
`In support of the proposed 24 month drug product expiry,
`the
`
`OPQ—XOPQ-TEM—0001v04
`
`Page 2 of 3
`
`Efiecfive Date: 14 February 2017
`
`Reference ID: 4266336
`
`

`

`QUALITY ASSESSNIENT
`
`applicant has proviled 24 months of long term and 6 nnnth of accelerated stability
`data. All data was acceptabh. Accordingly, Eagle Phanmceutizab proposed and the
`FDA accepts the expiration dating period of 24 months for the drug product when
`stored at stored between 2 -8 C (36 to 46 F) in the commercial packaging based on
`real time data.
`
`Microbiology:
`The resubm'ssion inchded lpdated details pertaining to process and micro validation.
`The micro team reviewed the submsion and it was concluded fliat all infir-tion
`
`provided by the applicant was adequate and as such the application '3 recomnended lbr
`approval on file basis of sterility assuance (see appended microb'nbgy 11mm).
`
`Facilities:
`
`All facilities_are ACCEPTABLE and recommended tbr approval ibr the fimctions
`listed in the application
`
`mm... m...
`
`“who,“ >1..:w.
`.
`rum“.
`
`..
`
`summit." Ovuvntl Marvtulwmg rm-«y sum
`umn “Wax... Luluvlimnirhlm “,uu-M-v-thx
`aw»
`Mmmmmm
`
`wp
`
`|-,1
`
`yum-«w» Munmxiulf‘fi um».
`
`(I), (4)
`
`C. Special Pmduct Quality Labeling Recommendations (NDA only)
`n/a
`
`D. Final Risk Assessment (see Attachment)
`n/a
`
`OPQ—XOPQ-TEM—0001v04
`
`Page 3 of 3
`
`Eflecfive Date: 14 February 2017
`
`Reference ID: 4266336
`
`

`

`Sherita
`McLamore
`
`Digitally signed by Sherita McLamore
`Date: 3/15/2018 01:15:49PM
`GUID: 503257950000415755492db5bb8b1a5c
`
`Reference ID: 4266336
`
`

`

`Memorandum
`
`NDA 205—580
`
`To:
`
`CC:
`
`From: A. K. Mitra, Ph.D. through A. Banerjee, Ph.D.
`
`Date:
`
`3/5/2018
`
`Re:
`
`Resubmission, dated 31-JAN—2018
`
`The original NDA 205-580 was tentatively approved on 02-JUL-2014, pending patent expiry
`of the listed drug. The resubmission application cover memo states the following: “It should
`be noted that certain modifications have been proposed for the drug product specifications,
`based on the following approved post-marketing CMC submissions for BENDEKA
`(bendamustine hydrochloride) injection 100mg/4mL (25 mg/mL) for infusion in a 50 mL
`admixture under the Eagle NDA 208194 (approved on December 7, 2015- Table 1).
`BENDEKA is the same formulation and uses the same container/closure system as
`Bendamustine Hydrochloride Injection.
`
`Table l
`
`Postmarketing Submissions Approved Under NDA 208194
`
`Postmarketing
`Submission
`Submission
`Approval
`Approved Change
`
`Submission
`Tale
`Date
`Date
`
`(1')“?
`
`To increase the long-term Stabitiiii‘i
`Supplement 8-
`.
`I,
`.“1
`or
`.‘7
`for the implu‘ity of
`’
`004 (SNOOSS)
`PAS
`ll 14 -016
`0-16-017
`“(4)
`
`
`Supplement 8-
`007 (SNOO66)
`
`.
`PAS
`
`.“1
`-‘,
`0“ 10 "017
`
`To provide specifications for
`n {7
`08' "5' ”017 With [units 01
`respectively.
`
`M(4)“)w:
`
`WW
`
`As noted above, a Reviewer’s Guide is provided that lists the summaries of the proposed
`changes, including the information provided for approval of the supplements listed in Table
`1, under NDA 208194. All documentation submitted under NDA 208194 to support these
`changes is included herein. Please note that, since the establishment of these specifications
`and limits was after testing of the registration batches was completed, batch analysis data and
`stability data provided for the registration batches ZBMOI l, ZBM012, and ZBM013, in
`Section 3.2.P.5.4 and Section 3.2.P.8.3 of this submission will not reflect these updates”.
`
`Reference ID: 4266336
`
`

`

`March 5, 2018
`
`Therefore, the review of the entire CMC submission was not conducted thoroughly again
`because of two month PDUFA goal date on the resubmission. However, due to the current
`OPQ policy on resubmissions for implementation of USP<232> and USP<233>, the
`elemental impurities specification in the drug product was verified. The current specification
`for the drug product including the supplemental changes for NDA 205-580 is recorded
`below.
`
`Summary of Bendamustine HCI Injection, 25mgImL
`S . -cifications for Release and Shelf-Life Testin .
`
`By HPLC: In the HPLC assay, the UV spectrum of the analyte peak in the
`sample solutioncxhibitsthcsamemaximaasthoseindleUV spectmmofthe
`standard.
`
`
`
`Single Unknown impurity:
`Total impurities:
`
`2 10 mm NMT mmparticles
`Z 25 um: NMTmmpanicles
`—Rc1casconly:NLT " --
`S_edle
`—NMT “EU/ms
`
`Refenence ID: 4266336
`
`

`

`March 5, 2018
`
`Sun-ary of Bendamustine HCl Injection, 25mymL Specifications for Release and Shelf-Life Testing
`(cont.)
`
`Release only:
`
`Elemental Impurities:
`
`(It) (4)
`
`'Not intended for every batch at release. In-Use stability studies performed on the 3 registration batches at
`the end of expiry.
`
`Reviewer’s comment: Since the applicant chose the option of drug product analysis based on
`the maximum daily dose compared to the PDE, the applicant included elemental impurities in
`the drug product specification. The acceptance criteria of the elements are all below PDE for
`individual elements for a parenteral drug product.
`
`The established name and the strength expression do not meet the USP salt policy of
`expression of strength based on the active moiety and not the salt. However, this non-
`compliance is widespread and several approved generics and 505(b)2 bendamustine drug
`products are already in the market with the expression of strength based on salt and not the
`active moiety. Therefore, this issue was discussed at the interdisciplinary labeling meeting.
`The clinical team wanted to keep the current expression with the View that the
`implementation of salt policy may have medical error implication. In addition, there are
`historical reasons for keeping the strength expression based on salt. Therefore, the strength
`expression on the label and on the submission, is not changed.
`
`Since rest of the resubmission is based on the approved supplemental information above, no
`further review of the resubmission is conducted. The drug product reviewer recommends
`approval.
`
`Reference ID: 4266336
`
`

`

`Amit
`Mitra
`
`Anamitro
`Banerjee
`
`Digitally signed by Amit Mitra
`Date: 3/05/2018 10:51:01AM
`GUID: 502d1ab500002af97e86c5f6f3951edc
`
`Digitally signed by Anamitro Banerjee
`Date: 3/05/2018 10:55:05AM
`GUID: 5075764700003844b7bc89632228509f
`
`Reference ID: 4266336
`
`

`

`M E M O R A N D U M
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`
`
`DATE:
`
`
`
`03/14/2018
`
`Rabiya Halder
`Regulatory Project Manager
`CDER/OPQ/OPRO
`
`
`
`TO:
`
`
`
`
`
`
` Jonathan Burgos, Ph.D.
`FROM:
` Review Microbiologist
`
`
` CDER/OPQ/OPF/DMA/Branch 1
`
`
`
`
`
`THROUGH: Elizabeth Bearr, Ph.D.
`
`
` Review Microbiologist
`
`
` CDER/OPQ/OPF/DMA/Branch 1
`
`
`
`
`SUBJECT: NDA: 205580
`
`
`Submission Date: 01/31/2018
`
`
`Drug Product: Bendamustine Hydrochloride Injection 100 mg/4 mL (25 mg/mL)
`
`
`Applicant: Eagle Pharmaceuticals, Inc.
`
`Conclusion: The submission is recommended for approval on the basis of sterility assurance.
`
`In 31 January 2018, Eagle Pharmaceuticals, Inc. submitted an amendment to support the final approval
`of NDA 205580. The application was originally received in 01 July 2013 and it was recommended for
`approval in 02 July 2014 pending acceptable overall recommendation from the Office of Compliance.
`A review of the product quality microbiological data can be accessed in the NDA 205580 CMC and
`Microbiology Review document, dated 05 May 2014. Below is a review of the microbiological-
`relevant changes proposed in the current submission. The proposed changes, detailed in Reviewer’s
`Guide (Section 1.2), have been organized according to their respective common technical document
`sections.
`
`Section 3.2.P.3.1 (Manufacturers, [Page 1/3]) and 3.2.P.5.3, Validation of Analytical Procedures,
`[Page 1/2])
`
`An additional drug product stability testing facility was proposed. In the 2013 submission, stability
`testing was only performed at the manufacturing facility.
`
`
`
`
`
`Proposed Testing Facility:
`
`
`
`
`
`1
`
`Reference ID: 4266336
`
`(b) (4)
`
`

`

`MEMORANDUM
`
`Responsbb fin: Perbrm'ng I-IPIC identificathn and rehted substances studies. Mhrobiobghal-
`relevant
`stability studies will continue to be perfimmd at
`the nanlfictlm'ng ficility, -
`—, andwmnotbeperbmnedatmenew
`tesfing ficility.
`
`
`
`Reference ID: 4266336
`
`

`

`Jonathan
`Burgos
`
`Elizabeth
`Bearr
`
`Digitally signed by Jonathan Burgos
`Date: 3/14/2018 01:21:14PM
`GUID: 5720cefa00de0a9047ad977609e16ac3
`
`Digitally signed by Elizabeth Bearr
`Date: 3/14/2018 01:22:52PM
`GUID: 55370d1e00cfd67fc04d8bfbedbf3096
`
`Reference ID: 4266336
`
`

`

`Sherita
`McLamore
`
`Digitally signed by Sherita McLamore
`Date: 3/15/2018 01:22:01PM
`GUID: 503257950000415755492db5bb8b1a5c
`
`Reference ID: 4266336
`
`

`

` NDA 205580
`
`CMC & Microbiology REVIEW Review #1
`
`NDA 205580
`
`Bendamustine Hydrochloride
`
`Eagle Pharmaceuticals Inc.
`
`Drug Product Team Review:
`
`Erika Pfeiler, Ph.D. (Microbiology)
`Gaetan Ladouceur, Ph.D. (CMC)
`
`New Drug Microbiology Staff
`and
`
`Office of New Drug Quality Assessment
`(Division I Branch II)
`
`for
`
`The Division of Oncology Products
`
`Reference ID: 3506850
`
`Page 1 of 70
`
`

`

` "" NDA 205580
`CMC & Microbiology REVIEW Review # , ““52
`
`Table of Contents
`
`Table of Contents ..................................................................................... 2
`
`Chemistry and Microbiology Review Data Sheet ................................. 3
`
`Executive Summary ................................................................................. 7
`
`I. Recommendations ...................................................................................................... 7
`
`II. Summary of Chemistry & Microbiology Assessments ............................................ 7
`
`III. Administrative......................................................................................................... 8
`
`A. Reviewers’ Signatures {see electronic signature page} ....................................................... 8
`
`B. Endorsement Block {see electronic signature page} ........................................................... 8
`
`Chemistry & Nlicrobiology Assessment ................................................ 9
`
`I. Review of Common Technical Document-Quality (Ctd-Q) Module 3: ....................9
`
`P DRUG PRODUCT .................................................................................................... 9
`
`RI Description and Composition of the Drug Product ..........................................9
`
`P2 Pharmaceutical Development ...........................................................................9
`
`P3 Manufacture .................................................................................................... 23
`
`R4 Control of Excipients ......................................................................................38
`
`P5 Control of Drug Product .................................................................................39
`
`R6 Reference Standards or Materials47
`
`P.7 Container Closure System ..............................................................................47
`
`R8 Stability ........................................................................................................... 51
`
`II. Review of Common Technical Document-Quality (Ctd—Q) Module 1 .................. 58
`
`III. List of Deficiencies Communicated and Resolved ............................................... 66
`
`Reference ID: 3506850
`
`Page 2 of 70
`
`

`

` NDA 205580
`
`CMC & Microbiology REVIEW Review #1
`
`CMC & Microbiology Review Data Sheet
`
`1. NDA 205580
`
`2. REVIEW #11
`
`3. REVIEW DATE: 05-May-2014
`
`4. REVIEWERS:
`
`Erika A. Pfeiler, Ph.D., Microbiologist
`Gaetan Ladouceur, Ph.D., Chemist
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`IND 109789
`
`Pre-IND Meeting comments
`Type B teleconference
`Review Microbiology
`(Jessica G. Cole)
`EOP2 Meeting Comments
`EOP2 Meeting Minutes
`
`Document Date
`
`04-Nov-2010
`12-Nov-2010
`16-Nov-2010
`
`06-Dec-2012
`13-Dec-2012
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission 5 Reviewed
`
`DARRTS SD Number
`
`Document Date
`
`Original NDA Submission
`Amendment SR 001
`
`Amendment SR 004
`
`
`
`Amendment (SR 005)
`Amendment SR 008
`
`Amendment (SR 010)
`
`Amendment (SR 011)
`Amendment SR 012
`
`Amendment (SR 015)
`Amendment SR 016
`
`Amendment (SR 018)
`Amendment SR 019
`
`Amendment SR 020
`
`Amendment (SR 021)
`Amendment SR 022
`
`Amendment (SR 023)
`Amendment SR 027
`
`Reference ID: 3506850
`
`Page 3 of 70
`
`01-Jul-2013
`17-Jul-2013
`
`19-Jul-2013
`
`19-Jul-2013
`15-Oct-2013
`
`26-Nov-2013
`
`27-Dec—2013
`08-Jan-2014
`
`30-Jan-2014
`06-Feb-2014
`
`07-Mar-2014
`01-Ar—2014
`
`31-Mar-2014
`
`07-Apr-2014
`ll-A r—2014
`
`25-Apr-2014
`l3-Ma —2014
`
`

`

` ““52 NBA 205580
`CMC & Microbiology REVIEW Review # , ““1
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Eagle Pharmaceuticals Inc.
`50 Tice Blvd Ste 315
`
`Representative:
`Telephone:
`email:
`
`Woodcliff Lake, New Jersey 07677
`Foma Rashkovsky, Senior Director Regulatory Affairs
`201—326—5300
`frashkovsky@eagleus.com
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`NA
`
`Bendamustine Hydrochloride
`NA
`
`3 S
`
`a) Proprietary Name:
`b) Non-Proprietary Name:
`c) Code Name/# (ONDQA only):
`(1) Chem. Type/Submission Priority
`(ONDQA only):
`
`0 Chem. Type:
`
`0 Submission Priority:
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`505(b)(2)
`
`10. PHARMACOL. CATEGORY:
`
`Alkylating agent
`
`ll. DOSAGE FORM:
`
`Solution
`
`12. STRENGTH/POTENCY:
`
`100 mg/4 mL (25 mg/mL)
`
`13. ROUTE OF ADMINISTRATION:
`
`IV Infusion
`
`14. Rx/OTC DISPENSED:
`
`‘1 Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`
`SPOTS product — Form Completed
`
`\/ Not a SPOTS product
`
`Reference ID: 3506850
`
`Page 4 of 70
`
`

`

` "_“"‘ NDA 205580
`CMC & Microbiology REVIEW Review # w W
`
`16. CHEMICAL NAB/IE, STRUCTURAL FORlVIULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`- United States Adopted Name [USAN]:
`
`Bendamustine Hydrochloride
`
`- Chemical Name:
`
`lH-benzimidazole—Z-butanoic acid, 5- [bis(2—chloroethyl)amino]—methyl-,
`monohydrochloride, or
`
`4-{ 5-[Bis(2-chloroethyl)amino ]-1-methyl-1 H- benzimidazol-Z-yl} butanoic
`acid hydrochloride
`
`\
`
`Empirical
`Formula
`
`C16H21C12N302 ' HCl
`
`Molecular
`
`394.72 g
`
`3543-75-7
`
`
`
`CINN\©[\
`
`Reference ID: 3506850
`
`Page 5 of 70
`
`

`

` NDA 205580
`
`CMC & Microbiology REVIEW Review #1
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
` ITEM
`
`REFERENCED/
`
`
`
`information in
`
`
`the submission
`
`
`was found to
`
`
`be adequate in
`
`Microbiology
`
`Review #25.
`
`DARRTS Date:
`
`08/20/201 3
`
`
`
`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")
`
`B. Other Documents:
`
`DOCUNI
`
`APPLICATION E 109789
`
`18. STATUS:
`
`CONSULTS/ CMC
`RELATED REVIEWS
`
`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`Established namesatisfacto
`
`
`
`.—_—— Erika Pfeiler
`12/20/13
`Chn'stoher Sheth
`05/13/14
`ElsbethGChikhale
`05/02/14
`N/A
`
`Methods Validation
`
`DPA
`
`DMEPA
`EA
`
`'
`Cate - orical exclusion u nted.
`
`05/02/14
`
`in in Gao
`Gaetan Ladouceur
`
`DMEPA: Division of Medication Error Prevention and Analysis: DPA: Division of Pharmaceutical
`Analysis in St. Louis
`
`Reference ID: 3506850
`
`Page 6 of 70
`
`

`

` NDA 205580
`
`CMC & Microbiology REVIEW Review #1
`
`The Chemistry and Microbiology Review for NDA 205580
`
`The Executive Summary
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`From the perspective of Chemistry, Manufactlning and Controls (CMC) and
`Microbiology, this NDA is recommended for ‘approval’ pending acceptable overall
`recommendation from the Office of Compliance.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None
`
`11. Summary of Chemistry and lVIicrobiology Assessments
`
`A. Description of the Drug Substance and Drug Product
`
`(1) Drug Substance
`
`Refer to Dr. Joyce Crich’s review of NDA 205580 drug substance.
`
`(2) Drug Product
`
`(m4) solution formulation of
`The dmg product is a stable ready—to-dilute
`bendamustine hydrochloride. It contains 25 mg/mL of bendamustine hydrochloride, 5
`mg/mL of monothioglycerol as an
`mm), and 0.1 mL/mL of propylene
`glycol as a
`(mo in polyethylene glycol 400. The container closure system
`consists of a 5 mL glass vial withflggmm rubber stopper and 20 mm aluminum flip-off
`seal. The target filling volume 18
`
`The drug product is intended for multiple uses. It does not contain an antimicrobial
`preservative, but it demonstrates self-preserving characteristics. The applicant presented
`appropriate preservative effectiveness studies to demonstrate that the drug product in its
`undiluted form is microbiologically stable for a 28 day in—use period.
`
`(0) (4)
`(b) (4) The
`(b) (4)
`(b) (4)
`The drug product is sterilized by
`mm were ap ropriately validated. The equipment
`properties of the
`used for equipment and container closure
`m) is appropriately qualified and
`operated using validated loading patterns. Data from media fills performed in 2009
`(initial qualification) and 2013 (periodic requalification) indicate that the
`M“)
`process at this facility is in a state of microbiological control.
`
`Reference ID: 3506850
`
`Page 7 of 70
`
`

`

` ‘5'“ NDA 205580
`CMC & Microbiology REVIEW Review #1"'“’"
`
`Bendamustine is susceptible to hydrolysis and undergoes rapid degradation in the
`presence of water to form mainly one degradant. This degradant (HPl), which is also a
`metabolite, is significantly observed when the admixture is prepared for IV
`administration.
`
`A repeat of the in-use stability study was requested due to a significant discrepancy
`observed in the levels of I-IPl degradant between two concentrations of the admixture. It
`was later found by the applicant that an error was made in the calculation of HPl levels
`for that study. Nevertheless, the repeat of the in-use stability study was still performed
`because of the applicant’s original commitment. In the repeat in—use stability study, the
`results showed that the drug product produced proportional levels of the HP] impurity
`when compared side by side to the RID (Treanda®). The data support a post-dilution
`hold times of 3 hours at room temperature and 24 hours under refrigeration. No
`microbiological in—use stability data are necessary to support these hold times.
`
`No significant changes were observed in the long-term stability studies up to 18 months,
`but a single unknown impurity was out of specification at the end of the stability studies
`conducted under accelerated conditions. According to ICHQlA (R2), if a significant
`change occurs between 3 and 6 months’ testing at the accelerated storage condition, the
`proposed shelf life should be based on the real time data available from the long-term
`storage condition. Therefore, an expiration date of 18 months, under the recommended
`controlled room temperature storage conditions, is granted. Also, storage precautions are
`required as the drug product is light sensitive. The primary container must be kept in the
`secondary packaging in order to protect the drug product from light.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Bendamustine hydrochloride is an alkylating agent indicated for the treatment of cancer.
`It is a
`M“) 100 mg (25 mg/mL) bendamustine hydrochloride solution which is
`ready for further dilution in an IV solution.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`Approval:
`. The applicant provided satisfactory information on the manufacturing, control and
`stability of the drug substance (see CMC review by Dr. Joyce Crich).
`. The applicant provided satisfactory information on the manufacturing, controls and
`stability of the drug product.
`. The applicant provided satisfactory information on the microbiological quality of the
`drug product and manufacturing process.
`. The drug product and drug substance manufacturing sites recommendations are still
`pending.
`
`1]]. Administrative
`
`A. Reviewer’s Signature {see electronic signature page}
`B. Endorsement Block {see electronic signature page}
`
`Reference ID: 3506850
`
`page
`
`49 Page(s) have been Withheld in Full as b4 (CCIfrS) immediately following this
`
`Page 8 of 70
`
`

`

` "5'5 NDA 205580
`CMC & Microbiology REVIEW Review #lf'fl"
`
`II.
`
`Review of Common Technical Document-Quality (Ctd-Q) Module 1
`
`A. Labeling & Package Insert
`
`1. Package Insert
`
`(3) “Highlights” Section
`
`-_ Information Provided in NBA
`Drug name (201.57(a)(2))
`Proprietary name and established
`name
`
`(mo)
`
`Bendamustine HCl (
`Inadequate, “Bendamustine
`hvdrochloride ” should be used
`instead as per the RLD and the
`statement ‘
`(m4) ”should
`be removed as it is not an
`
`
`
`acceptable dosageform.
`For intravenous infusion
`
`Injection: 100 mg/4 mL
`
`(b) “Full Prescribing Information” Section
`
`# 3: Dosage Fonns and Strengths
`
`-_ Information Provided in NBA
`Available dosage fonns
`Strengths: in metfic system
`A description of the identifying
`characteristics of the dosage
`forms, including shape, color,
`coating, scoring, and imprinting,
`
`when applicable.
`
`100 mg/4 mL
`A clear and colorless to yellow
`solution
`
`Reference ID: 3506850
`
`Page 58 of 70
`
`

`

` "E'fi NDA 205580
`CMC & Microbiology REVIEW Review #lf‘e"
`
`#1 l : Description
`
`-_ Information Provided in NBA
`Proprietary name and
`Bendamustine HCl Injection
`established name
`(mo Inadequate,
`“Bendamustine hi-‘drochloride ”
`should be used instead, as per the
`RLD, and the statement
`“(
`mm) ” should be removed
`
`Dosage form and route of
`administration
`
`Active moiety expression of
`strength with equivalence
`statement (if applicable)
`Inactive ingredient information
`(quantitative, if injectables
`21CFR201.100(b)(5)(iii)), listed
`by USP/NF names.
`
`Statement of being sterile (if
`a 0 0 licable
`
`Phannacological/ therapeutic
`class
`
`Chemical name, structural
`formula, molecular weight
`
`as it is not an acceptable dosage
`form.
`
`Intravenous infusion
`
`Not applicable. The salt form is used
`to maintain consistency with the
`currently marketed drug.
`0.1 mL of propylene glycol, USP, 5
`mg of monothioglycerol, NF, and
`q.s. t0 1 mL polyethylene glycol
`400, NF.
`W"
`
`Included, acceptable.
`
`Alkylating drug.
`
`Provided, but the structuralformula
`should show subscript numbers for
`each atom.
`
`
`
`Other important chemical or
`physical properties (such as pKa
`or pH)
`
`Not included. Inadequate, “clear,
`colorless to yellow ” should be
`added.
`
`Reference ID: 3506850
`
`Page 59 of 70
`
`

`

` NDA 205580
`
`CMC & Microbiology REVIEW Review #1
`
`#16 & 17: How Supplied/Storage and Handling
`
`-_ Information ProvidedinNDA
`Strength of dosage form
`100 mg/4 mL
`Identification of dosage forms,
`The description in section 16.2
`e.g., shape, color, coating,
`was found inadequate, see the
`scoring, imprinting, NDC
`tracked changes below.
`number
`
`Special handling (e.g., protect
`from li . It
`
`Retain in original package until
`time of use to Irotest from li . It.
`
`Woodcliff Lake, NJ
`
`Manufacturer/distributor name
`
`Between 2° and 8° C (36° to 46° F)
`"” ‘4’
`
`(21 CFR 201-100(5))
`
`Eagle Pharmaceuticals, Inc.
`
`Product Reviewer Comment:
`
`- Section 16.2 was revised and is shown below:
`
`mm
`
`Reference ID: 3506850
`
`Page 60 of 70
`
`

`

` NDA 205580
`
`CMC & Microbiology REVIEW Review #1
`
`Process Reviewer Comment: Drug product is intended for dilution in 0.9% sodium chloride
`for injection USP or 2.5% dextrose/0.45% sodium chloride for injection USP. Dosage and
`administration instructions state that the product should be used within 24 hours when held
`under refrigeration or 3 hours when stored at room temperature (these times include
`administration time). Package insert states that in-use vials should be discarded after 28
`days. Patient endotoxin exposure from the drug product is shown below.
`
`Endotoxin exposure from the maximum drug product doses. Compiled from Proposed
`Packa ~ e Insert.
`
`Indication
`
`Route of
`Maximum
`Endotoxin
`Administration Product Dose Specification
`
`EU/maximum
`dosel
`
`EU/max‘mum EU/dose when
`dose when
`diluted in
`.
`0.9% Sodium
`.
`Chloride for
`Injection
`
`diluted in 2.5%
`Dextrose/0.45%
`Sodium
`.
`Chloride
`Injection, USP3
`
`over a (4)
`
`Chronic
`
`Intravenous — to
`
`Lymphocytic be diluted in
`Leukemia
`500 mL of 0.9%
`
`Sodium
`
`Chloride
`
`Injection, USP
`or 2.5%
`
`Dextrose/0.45%
`
`Sodium
`
`Chloride
`Injection, USP
`
`Indolent B—
`cell non-
`.
`Hodgkin
`Lymphoma
`
`resulting in-
`180 mg in a
`1.8 In2 adult
`
`(Administered
`over a 30
`
`120 mg/m ,
`resulting in
`216 mg in a
`1.8 in2 adult
`.
`.
`(Administered
`
`Parenteral injection endotoxin limit: 350 EU/hour for a 70 kg or 1.8 m adult
`2USP Monograph for Sodium Chloride Injection - NMT 0.5 EU/mL (250 EU/500 mL)
`3USP Monograph for 2.5% Dextrose/0.45% Sodimn Chloride — NMT 10 EU/gram
`dextrose (125 EU/500 mL)
`
`Process Reviewer Comment: The proposed in-use holding periods are acceptable from the
`standpoint of product quality microbiology. Endotoxin exposure from the drug product does
`not exceed limits set forth in USP <85>.
`m“)
`
`Reference ID: 3506850
`
`Page 61 of 70
`
`

`

`CMC & Microbiology REVIEW
`
`2.
`
`Immediate container labels (latest revision is shown):
`
`
`
`-_ Information Provided in NBA
`Proprietary name, established name
`Bendamustine HCl Injection
`(font size and prominence (21 CFR -).
`201 . 10(g)(2))
`
`DosageStrength —
`
`100 mg/4mL
`
`themain anel
`
`207.35 3
`
`3 i
`
`CFR201.17)
`
`Page 62 of 70
`
`Reference ID: 3506850
`
`

`

`““52 NBA 205580
`
`CMC & Microbiology REVIEW Review # , ““1
`
`Bar code (21CFR 201.25)
`
`2° and 8° C (36° to 46° F)
`
`Not provided. A bar code must be
`added.
`
`
`
`Name of manufacturer/distributor
`
`Manufactured by:
`
`Must be diluted prior to
`administration.
`
`Adequate.
`
`Product Reviewer Comment: CMC and DMEPA groups issued the following IR (sent to
`the applicant on 03/18/2014):
`
`1. Container Label:
`
`a. The drug barcode is often used as an additional verification before drug administration
`in the inpatient setting; therefore it is an important safetyfeature that should be part ofthe
`label wheneverpossible. Yourproduct has not been provided an exception, therefore we
`request you add the product barcode to each individual vial as requiredper 21 CFR
`201.25(b)(1)(ii).
`
`b. There is a possibility that the peel-back labels may become detachedfrom the product
`container under normal use. Therefore, we recommend that the peel-back label should be
`resealable, able to withstand repeated openings and closings without detaching itselffrom
`the product container, and able to withstand moisture without detachingfrom the product
`container.
`
`mm) ” since it is not an acceptable dosageform.
`c. Remove the statement "(
`d. Replace the name “Bendamustine HCl " by “Bendamustine Hydrochloride " as per the
`RLD.
`
`e. "(25 mg/mL) " should go underneath "100 mg/4 mL
`
`f. Add names ofall inactive ingredients. (The immediate container label should have names
`ofall inactive ingredients: 21 CFR 201.100(b) (5) and quantity iffor injectables unless the
`label is too small)
`
`2. Ferrule and cap oversea] label:
`Our review ofthe Failure Mode Eflect Analysis conducted by Drug Safety Institute
`indicates that theproposed bendamustineferrz .le and cap oversea] label contains the
`statement
`0' m. This statement may notprevent medication
`error Ifthe healthcare practitioner does not know that 25 mg/mL is a concentrated strength
`ofbendamustine. We recommend revising the statement
`mm)
`to “Dilute Before Using ” as suggested by the United States Pharmacopeia (USP) General
`Chapter <1 > Injections labeling standard.
`
`Reference ID: 3506850
`
`Page 63 of 70
`
`

`

`
`
`Product Reviewer Comment: CMC and DMEPA groups issued the following IR (sent to
`the applicant on 04/ l 1/2014):
`
`a. The "Hydrochloride ” part ofthe established name is in a difi'erentfont size and does not
`appear to be part ofthe drug name. Revise the drug name so that the entire drug name,
`“Bendamustine hydrochloride ” is presented in the samefont