`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`Approval Package for:
`
`
`
`APPLICATION NUMBER:
`NDA 208194/S-003
`
`
`
`
` Name: BendekaTM (bendamustine hydrochloride)
`Injection, 100 mg/4 mL (25 mg/mL).
`
`Sponsor: Eagle Pharmaceuticals, Inc.
`
`
`
`
` Approval Date: September 23, 2016
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`NDA 208194/S-003
`
`
`CONTENTS
`
`
`Reviews / Information Included in this Review
`
`
`
`Approval Letter
`Approvable Letter
`Labeling
`Division Director’s Memo
`Labeling Review(s)
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology / Toxicology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology & Biopharmaceutics Review(s)
`Other Review(s)
`Administrative and Correspondence Documents
`
`
`
`
`X
`
`
`
`
`
`X
`
`
`
`
`
`
`X
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`NDA 208194/S-003
`NDA 208194/8-003
`
`
`
`APPLICA TION NUMBER:
`
`
`
`
`
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`
`
` !" #$%%&
`'()*+,-./012++3
`
`
`456789:5;<5=8>?@=57ABCD=E
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`9785A8;8O8;?FLF>;1>YY78<8D?57'8Z(;>6)YY7@=5?@FD[A'()\N5?8N)>6>A?3B*+-WB
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`^FA<8?@=)=?[H(^)\OF;R8DN8J5[]8DN5<>A?@D8:LN;F=:7F;@N8\95;8D?8;57-++<60/<T
`[*P<60<T\E
`Q:@A_9;@F;)YY;FK57`A>YY78<8D?57D8ZN;>65YY7@=5?@FDY;FYFA8A?:8OF77FZ@D6=:5D68[A\G
`^FDN>=??:8@D2:F>A8
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`S8:5K8=F<Y78?8NF>;;8K@8ZFO?:@AA>YY78<8D?57D8ZN;>65YY7@=5?@FDEQ:@AA>YY78<8D?@A
`5YY;FK8NE
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`>DN8;*-^HI3-/E,+5DN3-/E,-E
`COLF>:5K85DLb>8A?@FDAB=577I5]@L5T5@bB9:5;<E(EBI86>75?F;LR>A@D8AA9;F=8AAX5D568;B5?
`[*/+\/+*2W-P3E
`1@D=8;87LB
`cdeeghheijejekelmnoiplqprigmsnehgret
`)D5<@?;FR5D8;u88B9:E(E
`R;5D=:^:@8OBR;5D=:CC[)=?@D6\
`vOO@=8FO'8Z(;>69;FN>=?A
`vOO@=8FO9:5;<5=8>?@=57w>57@?L
`^8D?8;OF;(;>64K57>5?@FD5DNI8A85;=:
`
`(b) (4)
`
`
`
`
`
`Anamltro
`
`
`
`
`
`Ban erj ee
`
`Digitally signed by Anamitro Banerjee
`Date: 9/23/2016 06:09:04PM
`
`
ÿ
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`
`GUID: 5075764700003844b7b089632228509f
`Comments: The changes proposed in he NDA 208194IS-003 is acceptable. This supplement may be approved.
`
`
`
`GUID: 5075764700003844b7b089632228509f
`Comments: The changes proposed in he NDA 208194IS-003 is acceptable. This supplement may be approved.
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`NDA 208194/S-003
`NDA 208194/8-003
`
`
`APPLICA TION NUMBER:
`
`
`
`
`
`
`
`CHEMISTRY REVIEWS
`CHEMISTRY REVIEWS
`
`
`
`
`Review #1
`NDA 208194/S-003
`Bendeka (bendamustine hydrochloride) injection
`
`Page 1 of 5
`
`Office of New Drug Products
`Division of New Drug Products I
`Review of Chemistry, Manufacturing, and Controls
`
`1. NDA Supplement Number: NDA 208194 / 8-003
`
`2. Submission(s) Being Reviewed:
`
`PDUFA
`
`.
`
`0052
`
`08/03/2016
`
`08/03/2016
`
`08/09/2016
`
`_09/06/2016 09/06/2016
`
`11/08/2016
`
`08/15/2016
`
`09/07/2016
`
`(b) (4) testing for
`3. Proposed Changes: Eagle proposed stopping the current in-house
`release of the drug substance and adopting the result from the vendor’s Certificate of
`Analysis (CoA).
`
`4. Review #: 1
`
`5. Clinical Review Division: DHP
`
`6. Name and Address of Applicant:
`Eagle Pharmaceuticals
`50 Tice Blvd., Suite 315
`Woodcliff Lake, NJ 07677
`Phone: 201-326-5300
`
`7. Drug Product:
`
`
`
`Dosage
`
`Route of
`
`Rx or
`
`Special
`
`
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`whSÿ `Yÿ &ÿ ")
`
`Bendeka (bendamustine
`
`.
`
`.
`
`100 mg/4 mL
`
`.
`
`.
`
`8. Chemical Name and Structure of Drug Substance:
`
`USAN: Bendamustine Hydrochloride
`Chemical Name: 1H—benzimidazole—2—butanoic
`
`acid, 5- [bis(2-chloroethyl)amino]-methyl-,
`monohydrochloride, or
`4-{ 5-[Bis(2-chloroethyl)amino ]-1-methyl-1 H-
`benzimidazol—2—yl} butanoic
`acid hydrochloride
`Molecular Formula: C15H21C12N302 - HCl
`
`(b) (4)
`
`
`' ÿ$% &'$(&
`w('!(&ÿx& !(Sÿ_Yd_( yÿzÿd_(
`whSÿ `Zÿ "(#ÿ& )
`MW: 394.72 (salt form)
`whSÿ `Yÿ &ÿ ")
`
`Bendeka (bendamustine
`
`.
`
`.
`
`100 mg/4 mL
`
`.
`
`.
`
`8. Chemical Name and Structure of Drug Substance:
`
`USAN: Bendamustine Hydrochloride
`Chemical Name: 1H—benzimidazole—2—butanoic
`
`acid, 5- [bis(2-chloroethyl)amino]-methyl-,
`monohydrochloride, or
`4-{ 5-[Bis(2-chloroethyl)amino ]-1-methyl-1 H-
`benzimidazol—2—yl} butanoic
`acid hydrochloride
`Molecular Formula: C15H21C12N302 - HCl
`
`(b) (4)
`
`
`
`Review #1
`NDA 208194/S-003
`Bendeka (bendamustine hydrochloride) injection
`
`Page 2 of 5
`
`9.
`
`10.
`
`Indication: For the treatment of Chronic Lymphocytic Leukemia (CLL) and Indolent B-Cell
`non- Hodgkin Lymphoma (NHL)
`Supporting/Relating Documents: NDA 208194 original submission
`
`ll.
`
`Consults: None
`
`12.
`
`Executive Summary:
`The applicant has submitted this manufacturing supplement to propose stopping the current
`in-house
`1") (“testing for release of the drug substance and adopt the result from the
`vendor’s Certificate of Analysis (CoA).
`
`(b) (4)
`MWtest results obtained by
`The applicant has conducted an evaluation of
`(drug substance vendor) and
`(b) ”(drug product manufacturer). Based on the review of
`results from multiple batches of bendamustine hydrochloride and the fact that
`(b) mis
`used as a
`(b) (4), the applicant determined that the
`(b) (4) testing
`performed by the vendor,
`6” (4) is adequate to monitor and control
`(b) (4) levels in
`the drug substance. There is no need for the additional confirmatory
`0’) (4) testing
`currently performed by the drug product manufacturer,
`(”mfor incoming drug substance
`lots. The test will remain as a release test on the (b) “’CoA and the
`(b) (4) level will
`congppéto be reviewed by
`(”wand Eagle QA prior to batch release and recorded on the
`
`0A.
`
`13.
`
`Conclusions & Recommendations:
`
`14.
`
`15.
`
`16.
`
`This manufacturing supplement is recommended for approval.
`
`Comments/Deficiencies to be Conveyed to Applicant: None
`
`Primary Reviewer:
`Nina Ni, Ph.D., CMC reviewer, Branch II, Division of New Drug Products I, Office of New
`Drug Products, Office of Pharmaceutical Quality (OPQ)
`
`I
`
`ina Ni, Ph.D.
`
`09/07/2016
`
`Secondary Reviewer:
`Anamitro Banerjee, Ph.D., Acting Branch Chief, Branch 11, Division of New Drug Products
`1, Office of New Drug Products, Office of Pharmaceutical Quality (OPQ)
`
`
`
`Review #1
`NDA 208194/S-003
`Bendeka (bendamustine hydrochloride) injection
`
`Page 3 of 5
`
`eptember 08, 2016
`
`CMC Assessment
`
`1. Background Information
`
`Bendeka (bendamustine hydrochloride) injection was approved for the treatment of Chronic
`Lymphocytic Leukemia (CLL) and Indolent B-Cell non- Hodgkin Lymphoma (NHL) on
`12/07/201 5.
`
`(”mtesting by
`(”mperforms
`In tl41e original NDA, the drug substance manufacturer,
`lb” )MS as part ofroutine batch release requirements. The drug product manufacturer,
`(b) (4), performs
`(DH )testing by a” “)MS as part of incoming drug substance release
`testing. Both sites use a specification of Not More Than
`(b) (4).
`
`H. Proposed Changes
`
`(b) (4) testing
`In this manufacturing supplement, the applicant determined that the
`(b) (4) levels in
`performed by the vendor,
`(b) ”is adequate to monitor and control
`a” (”testing
`the drug substance. There is no need for the additional confirmatory
`currently performed by the drug product manufacturer,
`6” (”for incoming drug substance
`lots. The test will remain as a release test on the (b)(4)COA and the
`(b) “level will
`continue to be reviewed by
`(b) (”and Eagle QA prior to batch release and recorded on the
`(b) “’CoA. The following data are provided by the applicant to support the proposed
`change:
`
`
`
`Review #1
`NDA 208194/S-003
`Bendeka (bendamustine hydrochloride) injection
`
`Page 4 of 5
`
`Table 3-1: Com - arisen o‘
`
`15001BR26E
`
`15002FR26E
`
`15003GR26E
`
`15004GR26E
`
`fl 15005PR26E I
`n 15007GR26E I
`We I
`
`15009HR26E
`
`150111R26E2
`
`10
`
`15012lR26E
`
`15013lR26E
`
`CoA.
`
`Conclusion: Adequate.
`The drug product manufacturer,— has conducted-test for total 11
`batches ofdrug substance manufactured by -1sing.48. The data show that all drug
`
`d the data are comparable between two testing
`substance batches met the specification for
`ndamustine HCl
`sites. It is noted that-is used as a
`drug substance. -levels should not increase or decrease during shipping or storage.
`
`Based on the data, Eagle determined that the -testiag performed by the vendor,-is
`adequate to monitor and control -levels in the drug substance. Therefore, the drug product
`manufacturer, -will not conduct in-house release testing for -when they release the drug
`substance. Instead, the testing result for -fiom 'JoA will be adapted into the-
`
`
`
`Review #1
`NDA 208194/S—003
`Bendeka (bendamustine hydrochloride) injection
`
`Page 5 of 5
`
`Based on:
`
`o
`
`21CFR21 l.84(d)(2): Each component shall be tested for conformity with all appropriate written
`
`specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a
`
`report of analysis may be accepted from the supplier of a component, provided that at least one
`
`specific identity test is conducted on such component by the manufacturer, and MEN—m
`
`.
`
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`
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`
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`
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`
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`
`_
`
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`
`11'
`
`ICH Q7 7.31 Good manufacturing practice guide for active pharmaceutical ingredients: Full
`
`analyses should be conducted on at least three batches before reducing in-house testing.
`
`has also updated both drug product specification and analytical procedure accordingly.
`
`ifi
`
`1' An 1
`
`i
`
`The applicant’s proposal does not comply with either ICH Q7 or 21CFR 211.84 (d)(2) since the
`
`reliability of CoA should be checked at regular intervals. The following information request was
`
`conveyed to the applicant on 08/30/2016:
`
`0 You have proposed to adopt testing result for
`
`(b) mfrom the vendor’s CoA to your CoA to
`
`release drug substance for in-house use. However, as per 21CFR211.84(d)(2) and ICH Q7 7.31,
`
`emu-119111 ‘
`
`.
`
`flab/sis when a reduced in-house testing approach is adopted to release in-coming material.
`Therefore, provide your plan to periodically verify the
`(b) (4)test in-house by your drug
`
`product manufacturer.
`
`The applicant has agreed to conduct the in-house
`
`0’) (4) test for release of the drug substance
`
`annually on the fust batch received and adopting results from the vendor’s CoA on the other subsequent
`
`batches for the year in the Amendment 0052, dated 09/06/2016, which deems acceptable. The applicant
`
`
`
`
`Baneuee
`
`Anamltro
`
`
` !"
`# !$
`
`Digitally signed by Nina Ni
`Date: 9/08/2016 10:38:36AM
`GUID: 502d1ab500002afobe642f8f37136920
`
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`Digitally signed by Anamilro Banerjee
`Date: 9/08/2016 10:40:26AM
`GUID: 5075764700003844b7bc89632228509f
`
`
` ÿÿ
`ÿ %
`
`Digitally signed by Anamilro Banerjee
`Date: 9/08/2016 10:40:26AM
`GUID: 5075764700003844b7bc89632228509f
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 208194/S-003
`
`
`
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
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`
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