CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
`209472Orig1s000
`
`
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`CMC Review Memo
`
`NDA: 209472 (SDN 30)
`Submission Date: 8/9/2019
`Drug Name: Pemfexy (Pemetrexed Injection)
`Dosage Form: 500 mg/20 mL (25 mg/mL)
`Applicant: Eagle Phannaceuticals, Inc.
`Submission Type: Resubmission/Class 1
`
`Background
`This is a 505(b) (2) application by Eagle Pharmaceuticals. The reference drug product is Eli Lilly
`and Company's Alimta (pemetrexed disodium) for injection (NDAs 021677 and 021462).
`PEMFEXY (pemetrexed injection) for intravenous use is a sterile, clear, colorless to yellow or
`green-yellow solution. Each mL contains: 25 mg pemetrexed diacid, 260 mg propylene glycol,
`up to 16.5-19.9 mg tromethamine, and water for injection. Additional tromethamine not
`exceeding 19.9 mg/mL and/or hydrochloric acid may be added for pH adju$tment. During last
`round of review, a shelf-life of 18 months was granted to the drug product, when packaged in the
`proposed packaging configuration and stored at 2-8°C (36-46°F). NDA 209472 is still under
`tentative approval.
`
`CMC information
`There is no new CMC information submitted in this resubmission.
`
`Labeling
`The updated revised labeling is acceptable from the CMC perspective.
`
`Action
`NAI.
`
`Reference ID: 4500770
`Reference ID: 4662511
`
`

`

`-------------------------------------------------------------------------------~------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`
`•••••••••••••••••-w•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••
`Isl
`
`Signature Page 1 of 1
`
`XINGWANG
`10/02/2019 04:30:52 PM
`
`ANAMITRO BANERJEE
`10103/2019 07:20:25 AM
`
`Reference ID: 4500770
`Reference ID: 4662511
`
`

`

`QUALITY ASSESSMENT
`
`Recommendation:
`
`APPROVAL
`
`NDA209472
`Review 1
`
`vial
`
`Route ofAdministration
`
`Intravenous In· ection
`Rx
`Ea le Pharmaceuticals Inc
`NA
`
`SUBMISSION(S)
`
`REVIEWED
`
`0001 1
`
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`Amendment
`
`Amendment
`Amendment
`Amendment
`
`DOCUMENT DATE
`
`DISCIPLINE(S) AFFECTED
`
`December 30, 2016
`
`Februa 21, 2017
`
`Februa 22, 2017
`
`A ril 14, 2017
`
`A ril 18, 2017
`
`Mi 12, 2017
`
`Ma 31, 2017
`
`June 02, 2017
`
`June 12, 2017
`
`June 23, 2017
`
`Au st 18, 2017
`
`Se tember 08, 2017
`
`Se tember 15, 2017
`
`
`CMC
`
`Dru
`
`Process
`Process
`Dru Product andFacili
`CMC
`
`Process
`
`Dru Substance
`
`Dru Substance
`
`
`DISCIPLINE
`Drug Master File/Drug
`Substance
`Dru Product
`
`PRIMARY REVIEWER SECONDARY REVIEWER
`Haripada Sarker
`Ben Stevens
`
`OPQ-XOPQ-TEM-0001 v04
`
`Page 1 of2
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSMENT
`
`
`Regulatory Business
`Process Manager
`Application Technical Lead
`Laboratory (OTR)
`ORA Lead
`Environmental
`
`Steve Kinsley
`
`Anamitro Banerjee
`NA
`NA
`XinizWanj!;
`
`NA
`
`NA
`
`Anamitro Baneriee
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 2 of2
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSMENT
`
`Quality Review Data Sheet
`
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`
`A. DMFs:
`
`DMF
`#
`
`Type
`
`Holder
`
`Type II
`
`Type III
`
`Type III
`
`TypeV
`
`TypeV
`
`Item
`Referenced
`
`Pemetrexed
`Drug Substance
`
`Status
`
`Adequate
`
`Date
`
`Review
`
`Completed
`9/18/2017
`
`Comments
`
`Review-1
`
`Adequate
`
`09/05/2017
`
`Per MAPP
`
`Adequate
`
`09/05/2017
`
`Y er_MAI>P
`,_
`
`Adequate
`
`09/05/2017
`
`Per MAPP
`
`Adequate
`
`09/05/2017
`
`Per MAPP
`
`-
`
`-
`-
`-
`-
`
`B. 0ther Documents: IND, RLD, or sis er aoo,fications
`
`. t
`DOCUMENT
`
`APPLICATION NUMBER
`
`NDA
`
`021462
`
`DESCRIPTION
`
`Listed drug (ALIMTA)
`
`2. CONSULTS
`
`NA
`
`
`OPQ-XOPQ-TEM-0001 v04
`
`Page 1of1
`
`Effective Date: 14 February 2017
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`
`
`
`Executive Summary
`
`
`
`
`
`I.
`
`
`
`
`
`Recommendations and Conclusion on Approvability
`
`
`
`
`
`
`
`
`
`
`
`
`This NDA is recommendedfor APPRO VALfrom the CMCperspective.
`
`
`
`
`
`
`
`
`
`
`
`
`Action letter language (to be communicated to the applicant):
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`An expiry dating period of 18 months may be granted for this drug product when
`storedm the proposed container closure system at 2-8°C(1(4Ehfi-46°F)
`
`
`
`
`
`
`
`
`
`
`
`
`
`11.
`
`
`
`
`
`
`Summary of Quality Assessments
`
`
`
`
`
`A. Product Overview
`
`
`
`
`
`
`
`
`
`
`
`
`This submission is a 505(b)(2) application, referencing the lyophilized (b) ‘4)
`
`
`
`
`
`
`
`
`
`
`
`formulation, Alimta (NDA 21462). The listed drug (LD) Alimta is available in
`
`
`
`
`
`
`
`
`100 mg and 500 mg single dose vials.
`
`
`
`
`
`
`
`
`
`
`
`
`The proposed Pemetrexed (as diacid) for Injection is a sterile single dose ready to
`
`
`
`
`
`
`
`
`
`
`
`dilute solution with a concentration of 25 mg/mL (500 mg/vial), intended for IV
`
`
`
`
`
`
`
`
`
`
`
`
`
`use. The solution is further diluted with 5% Dextrose in Water to a maximum of
`
`
`
`
`
`
`
`
`
`final pemetrexed concentration of 15 mg/mL prior to administration.
`
`
`
`
`
`
`
`
`
`
`
`
`
`The drug product15 a clear, colorless to yellow or greben-yellow solution free from
`visible particles presented'1n Typos)EZCIear Glass
`“Bottles. The product'IS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4contains no antimicrobial preservatives.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The applicant is relying on FDA’s finding on safety and efficacy for the listed
`
`
`drug Alimta.
`
`
`
`
`
`
`
`
`
`Proposed Indication(s) including
`
`
`
`Intended Patient Population
`
`
`
`
`
`Duration of Treatment
`
`
`
`
`
`of each 21-day cycle.
`
`
`
`
`
`
`
`
`
`
`1. Locally Advanced or Metastatic Nonsquarnous
`
`
`
`
`Non-Small Cell Lung Cancer
`
`
`
`
`
`Initial treatment in combination with
`.
`
`cisplatin.
`
`
`
`
`
`
`. Maintenance treatment of patients whose
`
`
`
`
`
`
`disease has not progressed after four cycles
`
`
`
`
`of platinum-based first-line chemotherapy.
`
`
`
`
`
`
`Afier prior chemotherapy as a single-agent.
`
`
`
`
`
`
`2. Mesothelioma: in combination with cis . latin
`
`
`
`
`
`
`
`For Combination Use: 500 mg/m administered as
`
`
`
`
`
`
`
`
`an intravenous infusion over 10 minutes on Day 1
`
`
`
`
`
`
`OPQ-XOPQ-TEM-0001v04
`
`
`
`
`
`Page 1 of 3
`
`
`
`
`
`
`
`Effective Date: 14 February 2017
`
`
`
`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`
`Maximum Daily Dose
`
`
`For Single Use: 500 mg/m2 administered as an
`intravenous infusion over 10 minutes on Day 1 of
`each 21-day cycle.
`See above
`
`Alternative Methods of
`
`Administration
`
`
`NA
`
`B. Quality Assessment Overview
`Drug substance:
`DMF
`(LOA provided) for
`The applicant refers to
`general properties and manufacturing information for the drug substance. The DMF
`was last reviewed by Dr. Haripada Sarker on September 19, 2017 and found to be
`adequate. The applicant provided specifications and batch data, however referred to
`the DMF for all other information.
`the drug substance manufacturing facility was found
`acceptable based on its inspectional history.
`The drug substance and facility reviewers recommended approval for this NDA.
`
`Drug Product:
`The drug product is composed ofpemetrexed diacid (25 mg/mL), propylene glycol
`(260 mg/mL), tromethamine (for pH adjustment), hydrochloric acid (for pH
`adjustment), water for injection as a vehicle
`
`Registration batches were manufactured at
`proposed for commercial batches.
`
`scale. A batch size ofup to
`
`is
`
`OPQ-XOPQ-TEM-0001 v04
`
`Page 2 of3
`
`Effective Date: 14 February 2017
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`
`Bottle stoppered
`
`The drug product is packaged in 20 mL Type Clear Glass
`with 20 mm Grey
`Stopper with a
`Blue 20 mm Flip-off seal.
`The applicant provided 12 months stability data under long term storage conditions,
`and 6 months stability data under accelerated storage conditions for three
`registration batches. Based on the data presented, 18 months ofexpiration dating
`period may be granted for the drug product when stored at 2°C to 8°C (36°F to 46°F).
`Based on in-use stability data provided in the application, the diluted solution may be
`stored under refrigerated conditions (2°C to 8°C) and at ambient conditions
`(temperature/light) for 48 hours.
`
`All the manufacturing and testing facilities were found acceptable based on inspection
`
`history.
`
`
`The applicant is requesting categorical exclusion for EA as per 21 CFR 25.21
`
`
`The drug product, process, microbiology, and facility reviewers recommended
`
`approval for this NDA.
`
`
`Biopharmaceutics:
`
`The biopharmaceutics review assessed the adequacy ofthe Applicant's biowaiver
`
`request for the proposed drug product, pemetrexed diacid. Per 21 CFR 320.24(b )( 6),
`
`the supporting data and information for the biowaiver request were evaluated and
`
`found to adequately support bridging ofthe proposed drug product to the LD
`
`(pemetrexed disodium).
`
`The Biopharmaceutics Reviewer recommends approval ofthis NDA.
`
`
`C. Special Product Quality Labeling Recommendations (NDA only)
`No labeling recommendations were made during this review cycle.
`The listed drug NDA holder is currently updating the PI. Hence, the labeling
`submitted in this application, which is consistent with the current label ofthe
`listed drug, was not reviewed.
`
`D. Final Risk Assessment (see Attachment)
`See attached.
`
`OPQ-XOPQ-TEM-0001 v04
`
`Page 3 of3
`
`Effective Date: 14 February 2017
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`E. List ofDeficiencies for Complete Response
`
`None
`
`Application Technical Lead Name andDate: Anamitro Banel'jee, Ph.D., October 02,
`2017
`
`OPQ-XOPQ-TEM-0001 v04
`
`Page 1of1
`
`Effective Date: 14 February 2017
`
`

`

`Digitally signed by Anamitro Banerjee
`Date: 10/02/2017 10:27:33AM
`GUID:5075764700003844b7bc89632228509f
`
`42 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`
`ENVIRONMENTAL ANALYSIS
`
`This NOA Application qualifies for categorical exclusion in accordance with 21 CFR
`25.31{a}, and as such, does not require the submission of an Environmental Analysis.
`To the best of Eagle Pharmaceuticals Inc. 's knowledge, no extraordinary circumstances
`exist, as described under 21 CFR 25.21 that would prohibit granting ofthe Claim of
`Categorical Exclusion.
`
`Reviewer's Assessment: Adequate
`
`
`The EA statement is adequate (confirmed with Dr. Raanan Bloom).
`
`
`Primary EA Reviewer Name and Date: Xing Wang, Ph.D., ONDP/DNDPl/NDPBll
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`Anamitro Banerjee, Ph.D., Acting Branch Chiet ONDP/DNDPl/NDPBll
`
`

`

`Xing
`Wang
`
`Digitally signed by Xing Wang
`
`Date: 9/05/201712:13:25PM
`
`GUID: 525daca300039122a4daaad45e49c6fb
`
`Digitally signed by Anamitro Banerjee
`Date: 9/05/2017 01 :51 :04PM
`GUID: 5075764700003844b7bc89632228509f
`
`

`

`QUALITY ASSESSMENT
`
`
`NDA 209472 Labeling Reivew
`
`
`1. Package Insert
`
`(Ji) "Hie:hlie:hts" Section (21CFR 201.57(a)_),____________ ____
`
`RO\ised: 1212016
`
`Item
`
`Reviewer's Assessment
`
`Information
`Provided in NDA
`~!~!!~-'?~__!!!J~l_!>_!"~g_!!!!~_<.:_~!>1:..~.'.!..~X~)l________
`----------------------------------------------
`Pemetrexed Injection,
`Proprietary name and
`Edit (see below)
`for intravenous use
`established name
`------------------------------ --------------------------- --------------------------------------------
`Dosage form, route
`See above
`of administration
`-------------------------------- ----------------------------- -----------------------------------------------
`NIA
`Controlled drug
`substance symbol (if
`annlicable)
`Dosage Forms and Strengths (201.57(a)(8))
`A concise summary
`500 mg vial for
`of dosage forms and
`injection
`strengths
`
`Inadequate
`
`Conclusion: Inadequate
`
`PEMFEXY (pemetrxed injection), for intravenous use
`
`Injection: 500 mg/20 mL (25 mg/mL) in a single-dose vial
`
`(b) (4)
`
`

`

`n
`
`
`
`
`_ I formation Provided in NBA
`1
`
`
`
`
`Available dosae forms
`
`
`
`
`
`
`
`
`500 m emetrexed 25 m/mL
`
`
`
`
`
`
`
`A description of the identifying Not provided.
`
`
`
`
`characteristics of the dosage
`
`
`
`forms, including shape, color,
`
`
`
`coating, scoring, and
`
`
`
`
`
`
`
`when a licable.
`
`QUALITY ASSESSMENT
`
`
`
`
`
`
`
`(b) “Full Prescribing Information” Section
`
`
`
`
`
`
`
`
`
`
`
`# 3: Dosage Forms and Strengths 121CFR 201.57gqg4n
`
`3
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`3
`
`
`
`
`
`
`
`I
`
`
`
`
`i —
`
`i
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`
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`
`
`#11: Description ngCFR 201.57§c[§12n
`
` has the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`chemical name N-[4-[2-(2-amino-4,7-dihydr0-4-oxo-lH-pyrrolo[2,3-d]pyrimidin-5-
`
`yl)ethyl]benzoyl]-L-glumatic acid.
`
`
`
`
`
`
`
`
`
`(b) (4) molecular formula 521C20H21N506 and fiimolecular weight of 427.41. The structural
`
`formula is as follows:
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`
`
`pOOH COOH
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`;
`7
`ellow or green-
`
`
`
`
`
`
`
`Each mL contains: 25 mg pemetrexed diacid,
`
`
`
`
`
`
`
`
`
`
`
`(b) ‘4) and water for injection.
`(b) ‘4) tromethamine
`260 mg propylene glycol,
`
`
`
`
`
`
`
`
`
`
`
`Additional tromethamine and/or hydrochloric acid may be added for pH adjustment.
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`QUALITY ASSESSMENT
`
`
`
`
`
`
`
`
`Proprietary name and established
`name
`
`
`
`
`
`Dosage form and route of
`administration
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Active moiety expression of
`
`
`
`strength with equivalence statement
`for salt if a licable
`
`
`
`
`
`
`Inactive ingredient information
`
`
`
`(quantitative, if injectables
`
`
`21CFR201.100(b)(5)(iii)), listed by
`USP/NF names.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`Adeuqate
`
`
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`
`
`
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`
`
`
`
`
`
`
`Chemical name, structural formula, Pemetrexed
`(b) (4) is a folate
`
`
`
`
`
`molecular weight
`analog metabolic inhibitor.
`Pemetrexed diacid
`
`
`
`
`
`
`
`has the chemical name N-[4-[2-(2-
`
`
`amino-4,7-dihydro-4-oxo-1H-
`pyrrolo[2,3-d]pyrimidin—5-
`
`
`yl)ethy1]benzoyl]-L-glumatic acid.
`(b) (4)
`
`
`(b) (4)
`
`
`
`
`
`
`
`If radioactive, statement of
`im - ortant nuclear characteristics.
`
`
`
`
`
`
`Other important chemical or
`
`
`
`
`physical properties (such as pKa,
`
`
`
`solubility, or pH)
`
`
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`
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`
`
`
`
`
`
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`
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`
`
`Color of the solution is provided.
`
`
`
`Tromethamine and hydrochloric
`
`
`
`
`
`
`acid may be added for pH
`ad‘ustment.
`
`
`
`
`Conclusion:
`
`
`
`
`
`
`
`
`
`
`
`Add pharmacological/therapeutic class of the drug. Drug product components are edited.
`
`
`
`
`
`
`
`
`
`
`#16: How Supplied/Storage and Handling 121CFR 201.57gc1117n
`
`
`
`
`16.1 How Supplied
`
`
`
`
`
`
`
`
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`
`PEMEFEXY (pemetrexed Injection) is a clear, colorless to yellow or green-yellow
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`(b) ‘4) solution supplied in single-dose Vials for intravenous use
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`NDC 42367-531-32: Carton containing one (1) single-dose Vial of 500 mg/20 mL (25
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`mg/mL)
`(b) ‘4) ..
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`16.2 Storage and Handling
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`Refrigerate at 2° to 8°C (36° to 46°F). Pemetrexed is a citotoxic drug. Follow applicable
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`special handling and disposal procedures.
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`1 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`
`
`
`CINE!)
`w m no» no 4 imA'l,‘ m “borw
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`
`omments on the Information Provided in
`NDA
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`500 mg/Vial
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`500 mg/vial
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`Not provided
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`Conclusmns
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`\
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`Adequate
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`Item
`
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`
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`size and prominence (21
`
`
`CFR 201 . 10(g)(2))
`
`Strength (21CFR
`
`
`01.10(d)(1); 21.CFR
`
`
`
`
`01.100(b)(4))
`
`
`
`I' oute of administration
`
`
`21.CFR 201.100(b)(3))
`
`
`
`
`et contentS* (21 CFR
`
`01.5 1(a))
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`
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`ame of all inactive
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`I 0t number per 21 CFR Reseved space for lot number
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`Adequate
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`- C
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`.
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`I
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`21 CFR 201.100 b 1
`
`Stmge
`not re: uired
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`DC number
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`(per 21 CFR 201.2)
`
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`I equired for all labels or
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`Not prov1ded
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`‘
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`7-
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`Refrigerate at 2°C-8°C (36°F to 46°F)
`(b) ‘4)
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`
`NDC 42367-531-32
`
`
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`(b) (4)_
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`Not provided
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`I: ar Code per 21 CFR
`
`201.25(c)(2)***
`
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`Marketed by: Eagle Pharmaceuticals, Inc.
`
`
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`
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`n anufacturer/distributor Woodcliff Lake, NJ 07677
`
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`‘
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`‘
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`‘
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`*21 CFR 201.51(h) A drug Shall be exempt from compliance with the net quantity
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`declaration required by this section if it is an ointment labeled “sample’ ’, “physician’s
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`sample”, or a substantially Similar statement and the contents of the package do not
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`exceed 8 grams.
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`
`**For solid oral dosage forms, CDER policy provides for exclusion of"oral" from the
`container label
`**Not required for Physician's samples. The bar code requirement does not apply to
`prescription drugs sold by a manufacturer, repacker, relabeler, or private label distributor
`directly to patients, but versions of the same drug product that are sold to or used in
`hospitals are subject to the bar code requirements.
`
`Conclusion: Inadequate
`The changes/edits will be conveyed to the applicant by OND.
`
`1 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`
`Item
`
`Comments on the Information Provided in
`NDA
`Proprietary name, established PEMFEXY (PEMETRXED INJECTION)
`name (font size and
`prominence (FD&C Act
`502(e)(l)(A)(i), FD&C Act
`502(e)(l)(B), 21 CFR
`201.10(g)(2))
`Strength (21CFR 201.lO(d)(l);
`21.CFR 201.100((d)(2))
`Net contents (21CFR201.51(a))
`Lot number per 21 CFR
`201.18
`Expiration date per 21 CFR Not provided
`201.17
`Name of all inactive ingredients are provided. Quantitavie
`Name of all inactive
`ingredient information is not provided.
`ingredients (except for oral
`drugs); Quantitative ingredient
`information is required for
`injectables)[ 201.IO(a),
`21CFR201.100( d)(2)]
`
`Not provided
`
`Conclusions
`
`Adequate
`
`500mg/20mL
`(25 mg/mL)
`See above
`Inadequate
`
`Inadequate
`
`Inadegute
`
`Adequte
`
`Adequate
`
`Sterility Information (if
`applicable)
`"Rx only" statement per 21
`CFR 201.100(d)(2), FD&C
`Act 503(b)(4)
`Storage Conditions
`
`NDCnumber
`(per 21 CFR 201.2)
`(requested, but not required
`for all labels or labeling), also
`see 21 CFR 207.35(b)(3)
`
`Rx ONLY provided
`
`Refrigerate at 2°C-8°C (36°F to 46°F)
`
`Inadeciute
`
`NDC 42367-531-32
`
`Adequte
`
`UPC code space reserved but not provided
`
`Only provided "Marketed by"
`
`Bar Code per 21 CFR
`201.25(c)(2)**
`Name of
`manufacturer/ distributor
`"See package insert for dosage Provided
`information" (21 CFR 201.55)
`NIA
`"Keep out of reach of
`children" (optional for Rx,
`required for OTC)
`
`Inadequate
`
`Inadeciuate
`
`Adequate
`
`NIA
`
`(b) (4)
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`
`Route of Administration (not
`required for oral, 21 CFR
`201.lOO(d)(l) and (d)(2))
`
`Must be futher diluted before administration
`
`J
`
`Adequate
`
`Conclusion: Inadequate
`
`The changes/edits will be conveyed to the applicant by OND.
`
`
`Reviewer's Assessment and Signature:
`
`Secondary Review Comments and Concurrence:
`
`(b) (4)
`
`

`

`Xing
`Wang
`
`Digitally signed by Xing Wang
`
`Date: 9/05/201712:14:15PM
`
`GUID: 525daca300039122a4daaad45e49c6fb
`
`Digitally signed by Anamitro Banerjee
`
`Date: 9/05/2017 01 :50:48PM
`GUID: 5075764700003844b7bc89632228509f
`
`33 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`
`BIOPHARMACEUTICS
`
`Product Background:
`
`NDA/ANDA: 209472
`
`Drug Product Name I Strength: Pemetrexed Injection 25 mg/mL, Injection
`
`Route of Administration: Intravenous
`
`Applicant Name: Eagle Pharmaceuticals, Inc
`
`Review Summary:
`Eagle Pharmaceuticals, Inc. 's proposed Pemetrexed Injection, 25 mg/mL, is a ready-to
`dilute (RTD) new formulation submitted in accordance with Section 505(b)(2) of the
`Federal Food, Drug, and Cosmetic Act. The listed drug (LD) is Eli Lilly's Alimta®
`(pemetrexed) for injection (NDA 021462, approved on 2/4/2004), 100 and 500 mg.
`The Applicant requests to bridge the proposed drug product to Alimta® under 21 CFR
`320.24 (b) (6) as stated in FDA's WRO letter dated 9/23/2016 (IND 126831)1•
`
`The proposed Pemetrexed Injection, 25 mg/mL is intended for the same indications as
`Alimta®. It is noted that the proposed pemetrexed injection is to be diluted directly with
`5% Dextrose
`in water, while Alimta®
`is supplied as
`lyophilized powder for
`reconstitution with 0.9% sodium chloride. The Applicant did not conduct any clinical
`studies.
`
`This review evaluates the following data in support of the Applicant's bridging request.
`
`• Drug substance
`The comparison between the pemetrexed diacid in the proposed drug product
`and pemetrexed disodium in Alimta® demonstrate that the structures of the
`drug substance are equivalent.
`
`• Drug product formulation
`Two excipients, Propylene Glycol and Tromethamine, are present in the
`proposed drug product and found not likely to affect the in vivo disposition of
`pemetrexed. The proposed formulation is therefore acceptable.
`
`• Physicochemical characteristics
`The proposed drug product has higher osmolality than Alimta® due to the
`the Applicant's
`presence of propylene glycol, which was evaluated in
`Hemolysis study and does not cause safety concerns. In addition, the
`physicochemical characteristics of the admixtures of Eagle's proposed drug
`product and Alimta® are similar.
`
`OPQ-XOPQ-TEM-0001 v04
`
`Page 1of8
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSMENT
`
`•
`
`In vitro Protein binding study
`Results of an in vitro protein binding study indicate that the proposed product is
`comparable to Alim ta®.
`
`Review Recommendation:
`From the Biopharmaceutics perspective, the Applicant has bridged the proposed drug
`product to Alimta® (pemetrexed disodium) IV injectable (infusion) under 21CFR
`320.24 (b) (6) and thus NDA 209472 for Pemetrexed for Injection is recommended for
`
`APPROVAL.
`
`
`List Submissions being reviewed: Original submission (12/30/2016)
`
`
`Highlight of Key Outstanding Issues from Last Cycle: NIA (First cycle)
`
`
`Concise Description of Outstanding Issues : None
`
`
`This proposed drug product was previously discussed in IND 126831 1. The Applicant
`was advised to bridge the proposed drug product to the listed drug, Eli Lilly and Co.'s
`NDA 021462 Alimta® (pemetrexed disodium) IV injectable (infusion), under 21CFR
`320.24 (b) (6).
`
`The firm provided the following data in this application.
`
`Drug Substance
`The drug substance in the proposed drug product is pemetrexed diacid, while the API in
`the listed drug Alimta® is pemetrexed disodium.
`
`Effective Date: 14 February 2017
`
`,_______
`
`(b) (4)
`
`5 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`List ofDeficiencies: None
`
`Recommendation: From the Biopharmaceutics perspective, the Applicant has bridged
`the proposed drug product to Alimta® (pemetrexed disodium) IV injectable (infusion)
`under 21CFR 320.24 (b) (6) and NDA 209472 for Pemetrexed for Injection is therefore
`recommended for APPROVAL.
`
`Primary Biopharmaceutics Reviewer Name and Date: Zhuojun Zhao, Ph.D. 812312017
`
`Secondary Reviewer Name and Date: Okpo Eradiri, Ph.D.812412017
`
`OPQ-XOPQ-TEM-0001 v04
`
`Page 8of8
`
`Effective Date: 14 February 2017
`
`(b) (4)
`
`

`

`Zhuojun
`Zhao
`
`Digitally signed by Zhuojun Zhao
`
`Date: 8/24/2017 03:57: 13PM
`
`GUID: 508da6fd000284770cf4eecbae074722
`
`Digitally signed by Okponanabofa Eradiri
`
`Date: 8/25/2017 11 :23:58AM
`
`GUID: 50bdfe8d00003559ede66be3fd299f65
`
`

`

`QUALITY ASSESSMENT
`
`
`
`
`MICROBIOLOGY
`
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`
`
`Product Background: This is a chemotherapy agent for the treatment of locally advanced or
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`metastatic Non-squamous Non-Small Cell Lung Cancer and Mesothelioma. It is manufactured
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`as a ready to dilute solution and provided in 20 mL vials
`(b) ‘4) (500 mg/vial).
`
`
`
`NDA:
`
`
`
`209-472
`
`
`
`
`
`
`
`
`
`
`Drug Product Name / Strength: Pemetrexed Injection 25 mg/mL
`
`
`
`
`
`
`Route of Administration: Intravenous
`
`
`
`
`
`
`
`Applicant Name: Eagle Pharmaceuticals, Inc.
`
`
`
`
`Manufacturing Site:
`
`
`
`(b) (4)
`
`
`
`Method of Sterilization:
`
`
`
`(b) ‘4)
`
`
`
`
`
`Review Recommendation: Adequate
`
`
`
`
`
`
`
`Review Summary: The drug product
`
`(b) (4)w; H)
`
`
`
`
`
`
`
`
`Highlight Key Outstanding Issues from Last Cycle: NA
`
`
`
`
`Remarks:
`
`
`
`
`
`
`
`
`
`
`
`(b) ‘4) was recently reviewed by the Division of Microbiology
`The proposed manufacturer
`
`
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`
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`
`
`
`
`(b) ‘4). The DMA review (File
`(b) (4)) was used to
`Assessment for NDA
`
`
`
`
`
`
`
`supplement the manufacturing information for the subject NDA.
`
`
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`
`
`
`
`
`
`
`
`
`Concise Description Outstanding Issues Remaining: NA
`
`
`
`
`OPQ-XOPQ-TEM-0001v04
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`
`Supporting Documents:
`for the Bacterial Endotoxin Reduction
`DMF
`: DMF update dated
`family of stoppers. The DMF was reviewed by
`studies for the
`the Division of Microbiology Assessment for the
`family on
`and
`determined that the DMF was adequate.
`
`: DMA review dated
`was a review of
`the same manufacturing facility and manufacturing line. The facility was acceptable.
`
`(Reviewer Note: there are instances where the subject application only provided the most recent
`
`process. In those instances, the cited DMA review
`re-qualifications to support the
`supports the facility and therefore additional information was not requested).
`
`List Number of Comparability Protocols (ANDA only): NA
`
`S Drug Substance: NA
`
`Reviewer's Assessment: Drug substance is not sterile.
`
`
`P Drug Product
`
`P.1 Description of the Composition of the Drug Product
`• Description of drug product - Sterile ready to dilute solution. The product is to be
`stored at 2-8°C. Provided as a 20 mL fill in a 20 mL vial. Diluted in -
`of 5%
`dextrose in water for administration.
`• Drug product composition - The composition of the drug product is in table 1 below
`(copied from Application Section 3.2.P.3.2 Table 1):
`
`Table 1: Batch Formula
`
`lngrt>die-nt
`
`Pemetrexed"
`
`Propylene Glycol, USP/EP
`
`Trnmethamine, USP/EP
`
`Hydrnchloric Acid. NF/EP
`
`Water for Injection, USP/EP
`
`Composition
`
`NDA Registration
`Batches
`
`I
`
`Pmposed Commercial
`Batches
`
`mg/ mL
`
`25
`
`26{)
`
`QS to pH
`
`Q_S_ to pH
`
`OPQ-XOPQ-TEM-0001 v04
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

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`(b) (4)
`
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`13 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`Reviewer's Assessment: Adequate; the study supports the proposed
`storing the diluted drug product in 5% Dextrose.
`
`time limit for
`
`Post-Approval Commitments: NA
`
`List ofDeficiencies: NA
`
`Primary Microbiology Reviewer Name and Date:
`Denise A. Miller 07128117
`Senior Microbiologist
`
`Secondary Reviewer Name and Date:
`Bryan Riley Ph.D.
`Acting Branch Chief
`
`OPQ-XOPQ-TEM-0001 v04
`
`(b) (4)
`
`(b) (4)
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`

`

`Denise
`
`Miller
`
`
`Bryan
`
`Riley
`
`
`Digitally signed by Denise Miller
`
`Date: 8/02/2017 08:48:35AM
`
`GUID: 508da7280002a5d546459b998253d1aa
`
`Digitally signed by Bryan Riley
`
`Date: 8/02/2017 08:54: 15AM
`GUID: 503450f200004f5816a1d3ae902b5e91
`
`

`

`QUALITY ASSESSMENT
`
`ATTACHMENT I: Final Risk Assessments
`
`A. Final Risk Assessment - NDA
`
`a) Drug Product
`
`From Initial Risk Identification
`
`Review Assessment
`
`Attribute/
`CQA
`
`Sterility
`
`Endotoxin Pyrogen
`
`Factors that
`can impact the
`CQA
`• Formulation
`• Container closure
`• Process parameters
`• Scale/equipments
`•Site
`
`• Formulation
`• Container closure
`• Process parameters
`• Scale/equipments
`•Site
`
`Assay (API),
`stability
`
`Assay (anti­
`oxidant)
`
`Uniformity of Dose
`(Fill
`volume/delfverabl
`evolume)
`
`Osmolality
`
`• Formulation
`• Container closure
`• Raw materials
`• Process parameters
`• Scale/equipment
`•Site
`• Formulation
`• Raw materials
`• Process parameters
`•Scale/equipment
`•Site
`
`• Formulation
`• Container closure
`• Process parameters
`• Scale/equipment
`•Site
`• Formulation
`• Raw materials
`• Process parameters
`• Scale/equipment
`•Site
`
`H
`
`M
`
`L
`
`M
`
`L
`
`L
`
`Initial Risk
`Ranking
`
`Risk
`Mitigation
`Approach
`
`Final Risk
`Evaluation
`
`Acceptable
`
`Lifecycle
`Considerations/
`Comments
`
`Testing included Acceptable
`in DP release
`specification.
`Method
`supported by
`suitability
`studies.
`Included in DP
`specifications.
`
`Acceptable
`
`Large amount of Acceptable
`propylene glycol
`in formulation
`which has anti­
`oxidant property.
`DP stability data
`is ok.
`Fill volume
`Included in DP
`specifications
`
`Acceptable
`
`Acceptable
`
`The sponsor
`provided a
`hemolysis study
`report. Phann
`Tox assessed and
`had no concern
`because there
`were no
`
`OPQ-XOPQ-TEM-0001 v04
`
`Page 1 of2
`
`Effective Date: 14 February 2017
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
`
`
`differences
`detected in the
`hemolytic
`potential and
`plasma
`compatibility of
`Pemetrexed
`Injection in
`human whole
`blood relative to
`Alimta.
`Included in DP
`specifications.
`
`Acceptable
`
`Included in DP
`specifications.
`
`Acceptable
`
`Included in DP
`specifications.
`
`Acceptable
`
`Acceptable
`
`Extractable study
`reports ofglass
`vials and
`stoPI>ers from
`
`Included in DP
`specifications.
`
`Acceptable
`
`pH (High)
`
`pH (Low)
`
`Particulate Matter
`
`Leachables
`extractables
`
`Appearance
`(color/turbidity)
`
`• Formulation
`• Container closure
`• Raw materials
`• Process parameters
`• Scale/equipment
`•Site
`• Formulation
`• Container closure
`• Raw materials
`• Process parameters
`• Scale/equipment
`•Site
`• Formulation
`• Container closure
`• Raw materials
`• Process parameters
`• Scale/equipment
`•Site
`• Formulation
`• Container closure
`• Raw materials
`• Process parameters
`•Scale/equipment
`•Site
`• Formulation
`• Raw materials
`• Process parameters
`• Scale/equipment
`•Site
`
`L
`
`L
`
`M
`
`L
`
`L
`
`Anamitro Banerjee -5 0.9.2342.19200300.100.1.1 =2000423276, cn=Anamilro Banerjee -s
`
`Digitally signed byAnamllro Bane<Jee·S
`
`DN:e=US, 0=US. Gmlemml!Tll,o<>:HHS,OU=FDA, OU=Pl!Ople,
`
`
`Date: 2017 .10.02 15:37:58--04'00'
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 2 of2
`
`Effective Date: 14 February 2017
`
`(b) (4)
`
`