CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208194Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`Eagle Phamlaceuticals, Inc.
`
`QUALITY ASSSSlVIENT
`Bendeka (bendamustine hydrochloride) injection
`
`Recommendation: Approval, pending an acceptable recommendation
`from the Office of Study Integrity and Surveillance (OSIS) of the
`bioequivalence clinical site inspections
`
`NDA 208194
`
`Review #1
`
`Dru. Name/Dosa-e Form
`mm—n_
`
`DOCUMENT DATE
`
`
`
`02/13/2015
`
`03/03/2015
`
`03/18/2015
`
`04/02/2015
`
`06/25/2015
`
`07/09/2015
`
`07/14/2015
`
`08/11/2015
`
`09/01/2015
`
`09/14/2015
`
`0017
`
`0018
`
`0019
`
`0020
`
`0021
`
`

`

`Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSlVIENT
`Bendeka (bendamustine hydrochloride) injection
`
`Quali Review Team
`DISCIPLINE
`REVIEWER
`
`BRANCH/DIVISION
`
`REVIEW
`
`RECOMMENDATION
`
`Drug Substance
`
`Microblology
`
`Biopharmaceutrcs
`
`Nina Ni
`
`Nina Ni
`
`Vidya Pai
`Vinayak
`Pawar
`
`Zhong Li
`Jing Li
`
`Branch II/DNDPl/ONDP
`
`Branch II/DNDPl/ONDP
`
`Branch VII/DPAIII/OPF
`
`MABI/DMA/OPF
`
`Approval
`A o oroval
`
`Approval
`Approval
`
`IABIHDIA/OPF
`
`BBI/DB/ONDP
`
`Approval
`Approval pending an
`acceptable OSIS
`recommendation
`
`Business Process
`
`Rabiya Laiq
`
`BranchI/DRBPMI/OPRO
`
`NA
`
`
`
`Manager
`Application
`Technical Lead
`
`Laboratory (OTR)
`ORA Lead
`
`Janice Brown
`
`Branch II/DNDPl/ONDP
`
`Approval pending an
`acceptable OSIS
`recommendation
`
`N/A
`
`N/A
`
`N/A
`
`Paul Perdue Jr.
`
`MDTP/DMPTPO/OMPTP
`
`Environmental
`
`Janice Brown
`
`Branch II/DNDPl/ONDP
`
`Assessment (EA)
`
`See facility review
`recommendation
`
`Categorical exclusion
`accepted
`
`

`

`Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`
`Table of Contents
`
`Table of Contents .......................................................................................... 3
`
`Quality Review Data Sheet .......................................................................... 4
`
`Executive Summary ...................................................................................... 5
`
`Primary Quality Review............................................................................. 13
`
`ASSESSMENT OF THE DRUG SUBSTANCE ............................................................. l3
`
`2.3.S
`
`DRUG SUBSTANCE ............................................................................ 13
`
`ASSESSMENT OF THE DRUG PRODUCT .................................................................. 37
`
`2.3.P
`
`DRUG PRODUCT .................................. Error! Bookmark not defined.
`
`R.2
`
`Comparability Protocols ......................................................................... 37
`
`ASSESSMENT OF THE PROCESS ................................................................................ 38
`
`2.3.P
`
`DRUG PRODUCT ................................................................................. 38
`
`R2
`
`Comparability Protocols ......................................................................... 59
`
`ASSESSMENT OF THE FACILITIES ............................................................................ 60
`
`2.3.S
`
`2.3.P
`
`DRUG SUBSTANCE ............................................................................ 60
`
`DRUG PRODUCT ................................................................................. 61
`
`ASSESSMENT OF THE BIOPHARMACEUTICS INFORMATION ........................... 64
`
`ASSESSMENT OF MICROBIOLOGY ........................................................................... 72
`
`2.3.P.6
`
`Reference Standards or Materials ........................................................ 85
`
`A
`
`APPENDICES ..................................................................................................... 85
`
`A2
`
`Adventitious Agents Safety Evaluation ................................................. 85
`
`I.
`
`Review of Common Technical Document-Quality (Ctd-Q) Module 1 ................ 88
`
`Labeling & Package Insert ................................................................................................ 88
`
`II.
`
`III.
`
`IV.
`
`List of Deficiencies To Be Communicated ............ Error! Bookmark not defined.
`
`Attachments .......................................................................................................... 97
`
`Administrative....................................................................................................... 99
`
`

`

`Eagle Phannaceuticals, Inc.
`
`QUALITY ASSSSlVIENT
`Bendeka (bendamustine hydrochloride) injection
`
`Quality Review Data Sheet
`
`1. LEGAL BASIS FOR SUBMISSION: 505(b)(2)
`
`2. RELATED/SUPPORTING DOCUNIENTS:
`
`A. DMFs:
`
`
`
`
`DATE REVIEW
`COMPLETED
`05/06/2014
`
`N/A
`
`N/A
`
`N/A
`
`
`
`ENTS
`C0
`Reviewed by Joyce
`Crich
`
`Adequate information
`provided in the NDA
`Adequate information
`provided in the NDA
`
`Adequate information
`provided in the NDA
`
`DMF# TYPE HOLDER
`
`
`ITEM REFERENCED STATUSl
`
`
`
`[II
`
`
`
`[H
`
`
`
`Adequate, Adequate with Information Request. Deficient. or N/A (There is enough data in the
`application, therefore the DMF did not need to be reviewed)
`
`B. Other Documents: IND, RLD, or sister applications
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`205580
`
`“"0
`
`3. CONSULTS: None
`
`DISCIPLINE
`
`Biostatistics
`
`Pharmacology/Toxicology
`
`CDRH
`
`COMMENDAIION
`
`Clinical _
`
`_
`
`___
`
`

`

`Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`
`1.
`
`Recommendations
`
`Executive Summary
`
`NDA 208194, Bendamustine hydrochloride injection is recommended for approval fiom
`a product quality perspective, pending an acceptable recommendation from the Office of
`Study Integrity and Surveillance (0818) of the bioequivalence clinical site inspections.
`
`Include the following statement in the action letter:
`
`A shelf life of 24 months is granted for Bendeka (bendamustine hydrochloride) Injection,
`when stored in refrigerator at 2 - 8°C (36 - 46°F), protected from light.
`
`A. Recommendation and Conclusion on Approvability
`
`1. Summary of Complete Response issues: Not applicable.
`
`2. Action letter language, related to critical issues such as expiration date:
`Refer to section I above.
`
`3. Benefit/Risk Considerations
`
`The risks associated with product quality have been described and adequately controlled
`to assure the quality of the drug product and consistent clinical performance. Based on
`the data provided, the quality of the bendamustine hydrochloride injection drug substance
`and drug product is considered acceptable. Pending an approval recommendation of the
`bioequivalence clinical site inspections from the Office of Study Integrity and
`Surveillance (0813) there are no unresolved quality issues which might have a negative
`impact on the risk benefit of this product.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`II.
`
`Summary of Quality Assessments
`
`

`

`Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`
`(mo
`NDA 208194 for bendamustine hydrochloride injection
`New information in NDA 208194
`
`includes a modification of the dose preparation and administration, allowing
`administration of the product in a smaller volume (50 mL admixture), and over a shorter
`time period (10 minutes) as well as providing three options for admixtures, including a
`new 5% dextrose diluent option for a sodimn—free dosing regimen.
`
`Eagle received tentative approval for NDA 205580 for bendamustine hydrochloride
`injection on July 2, 2014. NDA 205580 (govides for the administration ofbendamustine
`
`A. Drug Substance [Bendamustine hydrochloride] Quality Summary
`
`(hm DNA alkylating agent. It is a
`Bendamustine hydrochloride is a
`bifimctional mechlorethamine derivative containing a purine-like benzimidazole ring.
`Mechlorethamine forms electrophilic alkyl groups that form covalent bonds with
`electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The
`bifimctional covalent linkage leads to cell death. The applicant referenced the CMC
`information for bendamustine hydrochloride to DMF No.
`(mo DMF No.
`(m4) was
`reviewed and found adequate.
`
`1. Chemical Name or IUPAC Name/Structure
`
`The chemical name of bendamustine hydrochloride is lH-benzimidazole-Z-butanoic acid,
`5-[bis(2-chloroethyl)amino]-l methyl, mono hydrochloride. Bendamustine
`hydrochloride has the following structure:
`Cl
`
`CIA/N
`
`N\
`: N
`
`\
`
`' HCI
`
`OH
`
`0
`
`Molecular formula C16H%)C12N302 -HCl
`Molecular Weight 394.7(og/mol
`
`2. Properties/CQAS Relevant to Drug Product Quality
`
`(”N0
`Bendamustine hydrochloride is a
`A significant feature of bendamustine hydrochloride is its
`
`relatively poor solubility and susceptibility of hydrolysis in aqueous conditions.
`
`3. List of starting materials
`
`

`

`'
`
`A
`
`.
`
`QUALITY ASSSSMENT
`: (bendamustine hydrochloride) lnjéj
`Eagle Pharmaceuticals, Inc.
`
`
`
`

`

`l ”A.“
`
`,
`
`-
`
`Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSNIENT
`: (bendamustine hydrochloride) inj > w:
`
`B. Drug Product [Bendamustine hydrochloride Injection] Quality Summary
`
`1. Strength
`
`100 mg/4 mL (25 mg/mL)
`
`2. Description/Commercial Image
`
`Bendeka (bendamustine hydrochloride) injection is supplied as a sterile, clear, colorless
`to yellow ready-to-dilute solution in a multi-use clear glass vial.
`
`Bendeka is intended for intravenous infusion only after dilution with either of the
`following:
`
`o 0.9% Sodium Chloride Injection, USP (normal saline); or
`
`o 2.5% Dextrose/0.45% Sodium Chloride Injection, USP; or
`
`o 5% Dextrose Injection, USP.
`
`3. Summary of Product Design
`
`Bendeka (bendamustine hydrochloride) injection is a ready—to—dilute non-aqueous
`solution formulation of Bendamustine hydrochloride intended for intravenous
`administration afier further dilution in 50 mL bag of either 0.9% Sodium Chloride
`Injection, USP, 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, or 5% Dextrose
`Injection, USP.
`
`The formulation contains excipients chosen to minimize potential stability issues.
`Bendamustine is susc
`tible to h drol
`is and under oes
`id de
`tio
`
`
`
`
`
`was able to minimize the formation of impurities, particular]
`impurities, in bendamustine hydrochloride injection formulation.
`
`the
`
`

`

`QUALITY ASSSSNIENT
`: (bendamustine hydrochloride) inj -
`
`.
`
`*
`
`-
`
`Eagle Pharmaceuticals, Inc.
`
`4. List of Excipients
`
`Each milliliter of Bendeka (bendamustine hydrochloride) injection contains 25 mg of
`bendamustine hydrochloride, 0.1 mL of propylene glycol, USP, 5 mg of
`monothioglycerol, NF_ polyethylene glycol (PEG) 400, NF. Sodium
`hydroxide may have been used to adjust the acidity of PEG 400.
`
`The excipients monothioglycerol, propylene glycol, polyethylene glycol 400 and sodium
`hydroxide which are inactive ingredients present in many FDA approved intravenous
`injection drug products. The levels, in terms of concentration in the drug product and the
`admixture of excipients are below the levels used in currently approved parenteral drug
`products and do not require qualification.
`
`5. Process Selection (Unit Operations Summary)
`
`
`
`

`

`QUALITY ASSSSNIENT
`: (bendamustine hydrochloride) inj -
`
`*
`
`-
`
`.
`
`Eagle Pharmaceuticals, Inc.
`
`7. Expiration Date & Storage Conditions
`
`A shelf life of 24 months is granted for Bendeka (bendamustine hydrochloride) Injection,
`when stored in refrigerator at 2 - 8°C (36 - 46°F), protected from light.
`
`Bendamustine hydrochloride is a multi-use vial. Although it does not contain any
`antimicrobial preservative, bendamustine hydrochloride is bacteriostatic and does not
`support bacterial growth. The partially used vials are stable for up to 28 days when stored
`in its original carton under refrigeration (2 - 8°C or 36 - 46°F). Each vial is not
`recommended for more than a total of six (6) dose withdrawals.
`
`'Ihe in-use stability for the 50 mL diluted product in 0.9% Sodium Chloride and 0.45%
`Sodium Chloride/2.5% Dextrose admixture solutions is 6 hours at room temperature and
`
`

`

`Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`
`24 hours at refrigerated conditions.
`
`The in—use stability for the 50 mL diluted product in 5% Dextrose Injection is 3 hours at
`room temperature and 24 hours at refrigerated conditions.
`
`8. List of co—packaged components
`
`There are no co—packaged components supplied with the drug product.
`
`9. Facility Review
`
`There are no significant, outstanding manufacturing risks and the Office of Process and
`Facilities recommended approval of the NDA submission. Based on firm inspectional
`history and district file review, the manufacturing facilities as listed below for NDA
`208194 are acceptable.
`
`Drug Substance Facilities
`1.
`2.
`
`Drug Product Facilities
`1.
`
`District Recommendation
`
`(mo Acceptable Based on District Recommendation
`(m4) Acceptable Based on Profile
`
`M" Acceptable Based on
`
`2.
`
`('mAcceptable Based on Profile
`
`C. Summary of Drug Product Intended Use
`
`
`Proprietary Name of the Drug Product
`
`Bendeka
`
`Non Proprietary Name of the Drug Product
`Non Proprietary Name of the Drug Substance
`
`bendamustine hydrochloride injection
`bendamustine h drochloride
`
`Proposed Indication“) including Intended
`Panel" P°P“l"“°n
`
`intravenous] over 10 minutes on Da 3 1
`
`0 Chronic lymphocytic leukemia (CLL).
`Efficacy relative to first line therapies
`other than chlorambucil has not been
`
`established.
`
`Indolent B-cell non-Hodgkin lymphoma
`(NHL) that has progressed during or
`within six months of treatment with
`
`rituxirnab or a rituximab-containing
`regimen.
`
`Duration 0f Treatment
`
`Treatment continues until disease——
`
`

`

`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`Eagle Pharmaceuticals, Inc.
`
`and 2 of a 21—day cycle, up to 8 cycles Alternative Methods of Administration
`
`and 2 of a 28-day cycle, up to 6 cycles
`
`For NHL: 120 mg/m2 infused
`intravenously over 10 minutes on Days 1
`
`D. Biopharmaceutics Considerations
`1. BC S Classification:
`
`0 Drug Substance: Not established
`
`0 Drug Product: Not established
`
`2. Biowaivers/Biostudies
`
`o Biowaiver Requests: N/A
`0 PK studies: A bioequivalence study comparing Eagle’s product
`and TreandaQ, the reference product, is reviewed.
`
`Based on FDA recommendations given in a meeting held on 1/15/2013, BE was based
`only on the AUCs for BDM, because the proposed product was intentionally formulated
`to exhibit different Cmax and Tmax compared to the Listed Drug (due to the difference
`in concentration and duration of administration). Bioequivalence was determined based
`on comparison of the bendamustine AUCs (AUC0_, & AUCOW) between the Test product
`and the Listed Drug. The Division of Biopharmaceutics recommends APPROVAL of
`NBA 208194 for Bendamustine Hydrochloride Capsules, 25 mg/mL.
`
`E. Novel Approaches: None
`
`F. Any Special Product Quality Labeling Recommendations:
`
`BENDEKA (bendamustine hydrochloride) Injection should be stored refrigerated at 2° to
`8°C (36° to 46°F). Retain in original carton until time of use to protect from light.
`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. Accordingly, the following statement was put on the vial and carton labels:
`“Retain in originalpackage until time ofuse. Protectfiom light.”
`
`G. Process/Facility Quality Summary (see Attachment A)
`
`H. Life Cycle Knowledge Information (see Attachment B)
`
`Digitally signed by Janice T. Brown —A
`DN: c=US, o=U.S. Government, ou=HHS, ou=FDA,
`
`ou=Peop|e, 0.9.2342.19200300.100.1.1=1300101685,
`cn=Janice T. Brown -A
`Date: 2015.1 1.05 13:24:01 —05'00'
`
`51 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`
`ASSESSNIENT OF THE BIOPHARMACEUTICS INFORMATION
`
`33. Are the in—vitro dissolution test and acceptance criteria adequate for assuring
`consistent bioavailability of the drug product?
`
`Not Applicable. The drug product is a solution for intravenous infusion and dissolution
`testing is not needed.
`
`34. Are the changes in the formulation, manufacturing process, manufacturing sites
`during the development appropriately bridged to the commercial product?
`
`The same formulation used throughout development is the intended commercial product.
`No bridging is therefore needed. The Biopharmaceutics review will focus on the
`Bioequivalence study comparing the Applicant’s product and Treanda®, the listed drug.
`
`The Applicant has developed a sterile solution of bendamustine hydrochloride G3DM
`HCl) for intravenous administration for the treatment of chronic lymphocytic leukemia
`(CLL) and indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or
`within 6 months of treatment with rituximab or a rituximab-containing regimen. The
`comparison between the proposed drug product and the LD, Treanda, in terms of physical
`properties and dosing regimen are summarized in the table below:
`
`Vial
`
`Table 34-1: Comparison of Eagle BDM HCl vs Treanda®
`Physical form
`Amount
`Volume
`Infusion
`volume
`
`Infusion time
`
`HCl
`
`dose
`
`solution
`
`min for NHL
`
`-----—-
`
`dose
`
`powder
`
`100 mg
`
`The Applicant conducted an open-label, randomized, crossover (3—period, partially
`replicated) phase 1 study (# EGL-BDM—C-l301) to demonstrate the bioequivalence of
`the drug product to the listed drug. The safety and tolerability profile of the two drug
`products were also assessed.
`
`BIOEQUIVALENCE STUDY EGL-BDM—C-l301
`
`Study Title:
`
`Phase 1, open-label, crossover, randomized, bioequivalence study to evaluate two
`formulations of Bendamustine (BDM) Hydrochloride (HCl) administered to cancer
`patients.
`
`

`

`Bendeka (bendamustine hydrochloride) injection Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSNIENT
`
`Objectives
`
`— To demonstrate the bioequivalence (BE) of between Eagle’s BDM HCl (Test
`product) and Teva’s BDM HCl Reference product).
`— To Evaluate the infusion-related safety and tolerability profile of Eagle BDM.
`
`— To characterize additional BDM phannacokinetic G’K) parameters of Eagle-BDM
`(T) and Teva-BDM (R), as well as PK parameters for the metabolite, gamma-
`hydroxy-bendamustine (M3)
`
`Design
`
`Open—label, randomized, partially replicated crossover (3—period, TRR, RTR, or RRT).
`
`Population: Cancer patients with histologically confirmed diagnosis of cancer (solid
`tumors and hematologic malignancies excluding chronic lymphocytic leukemia [CLL])
`who had progressed or relapsed on standard therapy, or for whom no curative or standard
`therapy was appropriate.
`
`Study Products:
`— Test: Eagle-BDM, 120l mg/mz, 50 mL given by IV infusion over 10 min.
`— Reference: Teva—BDM, 120 mg/mz, 500 mL admixture given by IV infusion over
`60 min.
`
`Sample size: Sixty (60) patients received all 3 doses of BDM. The sample size was
`calculated based on an interim analysis2 which showed that BDM is a highly variable
`drug (within subject CV% of BDM was 41 .987%), and 80% of power.
`
`Four (4) PK Evaluable (PKE) sub-populations were evaluated:
`— FDA-requested population for primary BE analysis: n=60, who received 3 doses
`of BDM, which included 22 patients who completed 3 doses but had major
`infusion-related deviations or PK sample collection deviations;
`
`— FDA-requested population for secondary BE sensitivity analysis: n=57, who
`received 3 doses of BDM, but excluding the 2 patients with major PK sample
`collection deviations and 1 patient with a major infusion-related deviation;
`
`1 In view ofthe shorter infusion time for Eagle-BDM resulting in a higher Cm and possibly impacting
`safety. the FDA requested that the highest approved BDM dose (120 mg/mz) be evaluated in this study.
`2 FDA has agreed on the interim analysis, which was planned for the first 12 patients (4 patients from each
`treatment sequence) completed randomized treatments, in order to estimate the within patient variability of
`Teva-BDM, estimate the ratio of geometric means, adjust study sample size to maintain the study power of
`280%. and review the safety assessment. (INDl 16448 Oflice of Clinical Pharmacology Review.
`03/20/2014)
`
`

`

`Eagle Pharmaceuticals, Inc. ‘ ummmtu'owm
`
`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`
`— Eagle original proposed population for primary BE analysis: n=44, who received
`3 doses of BDM without deviations, plus 6 patients with PK sampling deviation
`but used for interim analysis;
`
`— Eagle original proposed population for secondary BE sensitivity analysis: n=38,
`who received 3 doses of BDM Without deviations.
`
`Treatment Schedule and Sampling Time:
`
`”mg #
`
`Table 34-2 Treatment Schedule and Sampling Time
`8...]... T...
`
`initial dose
`
`
`
`E_
`
`Depending on
`randomization
`
`Cycle 2. day l
`“- EAGLE—BDM Cycle 2. day 2
`Note: one treatment cycle is 28-day
`
`Predose on day 1 (Dose 1) till 8 hours after
`the end of administration on day 2 (Dose 2)
`Predose till 24 hours after Dose 3
`No PK sampling
`
`Washout Period: 24 hours between the 1St and 2nd doses, which was justified by a short
`plasma elimination T‘/2 of approximately 40 minutes
`
`Blood Sampling: 15 to 30 minutes before infusion of Study Treatment; half-way through
`the nominal infusion period; immediately afler completion of the infusion (within 1
`minute); 5, 15, 30, and 45 minutes post infusion; and l, 1.5, 2, 3, 4, 5, and 8 hours post
`infusion. Additional PK blood samples were taken 24 hours from the start of infusion for
`Dose 1 and Dose 3 (Day 1 of both cycles).
`
`Bioanalm'cal Method and Validation
`
`Plasma BDM concentration was measured. Plasma concentrations of M3 (a minor active
`metabolite) were also measured but not analyzed for BE determination.
`
`Table 34-3 Bioanalytical Method and Validation
`
`Sample Volume Required.
`
`Storage Conditions.
`Extraction Procedure
`
`Five (5) mL blood samples were drawn from a peripheral vein in the opposite
`arm/side from the site of administration.
`
`Stored at -10 to -30 °C and -60 to -80 °C.
`Su gt . rted-li
`'d extraction
`
`10.0 to mow foam. a... 1.00 to moon/mt M3
`
`Analytical Methodology
`
`Supported liquid extraction/ LC-MS
`
`nominal concentration
`
`Regression Type
`coefficamtomamm
`
`Between-Batch Accuracy
`
`WWW...
`
`Weighted (lle) quadratic regression
`
`standards
`
`QCs
`
`NI'A
`
`Range of 115.0% bias (230.0% at LLOQ) of the
`
`

`

`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`Eagle Pharmaceuticals, Inc.
`
`standards
`
`NI'A
`
`Within-Batch
`
`Recovery
`
`Range of i15.0% bias (i20.0% at LLOQ) of the
`nominal concentration
`
`NMT
`
`MW. at LLOQ
`
`Accuracy
`
`CV
`BDM
`
`BDM— internal standard
`M3
`M3- Internal standard
`
`1 hour (RT). 2 hours (wet ice)
`5 cycles (-10 to -30 °C); 4 cycles (-60 to -80 °C)
`30days (-10 ~ -30 °C): 198 days (-60 ~ -80 °C)
`8 hours
`
`Stability in human plasma
`
`6 hours
`at room temp
`.
`.
`.
`35 da
`_10 to _30 °C
`Solution Stability
`6 hours
`at room temp
`.
`.
`.
`35 days
`-10 to _30 °C
`Reference Solution Stability
`LLOQ (Accuracy / CV) — 10.0 ng/mL for BDM. 1.00 ng<"n1L for M3
`
`Dilution Integrity (v:v sample-blank) —
`
`The Bioanalytical method was performed acceptably, and the method was appropriately
`validated.
`
`Pharmacokinetic Parameters and Statistical Analysis
`
`BE analysis: The BDM PK parameters for Eagle—BDM and Teva—BDM (AUCM, AUCM,
`Cm, Tm, and T15) were generated from the actual plasma concentration-time data using
`non-compartmental analysis for the above-mentioned 4 sub—. A statistical analysis was
`performed in the 2 Primary PKE sub-populations (n=60 [FDA requested primary] and
`n=44 [Eagle proposed primary]), as well as for the 2 secondary sensitivity populations
`(n=57 [FDA requested primary] and n=38 [Eagle proposed primary]) to determine
`whether Eagle-BDM was bioequivalent to Teva—BDM on the basis of total BDM
`exposures, AUCo_, and AUC”. It was decided on the internal meeting for IND116448
`held on 01/ 15/2013 that similarity in AUC is sufficient for concluding bioequivalence
`because cm (and Tm) will be difierent due to the difl'erences in concentration and
`administration duration between the formulations.3
`
`Both the unsealed and the reference-scaled average BE approaches were used in the
`analyses of the data. Per the Applicant, the within-subject variability (SWR) of the drug is
`more than 30%; the reference-scaled BE analysis was therefore relied upon to determine
`bioequivalence.
`
`Safety Assessment
`
`3 1ND116448 Memorandum of Meeting Minutes. 01/16/2013
`
`

`

`Bendeka (bendamustine hydrochloride) injection Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSMENT
`
`Eagle-BDM administered IV to cancer patients appeared to be safe and well tolerated in
`this study. The most common TEAEs reported for patients treated with either Eagle-
`BDM or Teva—BDM were either known treatment effects of BDM HCl or expected from
`the underlying disease condition.
`The higher Cmax values observed with the “short-infusion” Eagle-BDM product
`administered in this study produce a similar safety profile as the currently marketed
`Teva—BDM formulation and thus the PK safety link has been established. Refer to the
`Clinical Safety review for additional details.
`
`Results
`
`Bioequivalence: The mean PK profiles in semi-logarithmic scale comparing Eagle and
`Teva BDM are presented below for the FDA requested primary population (n=60) and
`the Eagle proposed secondary population (n=3 8) respectively.
`
`Figure 34-1 Primary PKE Population (FDA recommended) Mean BDM (iSD) Plasma Concentration-
`Time Comparative Profiles (0-8 Hours Truncated) Following a Single-Dose Infirsion of Eagle-BDM (10
`Minute Infusion) and Teva BDM (60 Minute Infusion) in “End of Life” Cancer Patients (Linear Scale/
`
`N=60)
`fura.)
`
`.........................................................
`
`Figure 34-2 Secondary Sensitivity PKE Population (Eagle Proposed per SAP) Mean BDM (:I:SD) Plasma
`Concentration- Time Comparative Profiles (0-8 Hours Truncated) Following a Single-Dose Infusion of
`Eagle-BDM (10 Minute Infusion) and Teva BDM (60 Minute Infusion) in “End of Life” Cancer Patients
`(Linear Scale/ N=38)
`
`

`

`Eagle Pharmaceuticals, Inc.
`
`
`
`WonPlasmaConcmtrmlm(HQ/IN]4/-ISO
`
`
`QUALITY ASSSSNIENT
`: (bendamustine hydrochloride) injecfi
`
`‘
`
`a
`
`l 5000
`
`
`
` ..——., fiflm 7—..—.._—'.— ' . .., .—..
`
`
`
`JO
`0
`‘0
`I20
`'00
`:00
`.360
`m
`‘90
`Tune Pom! (Mir-am cosheose)
`
`
`
`400
`
`As expected, Eagle-BDM Cmax values are approximately 250% higher than that of
`Teva-BDM. The total BDM exposure is nearly identical. The descriptive summary of the
`PK parameters can be found in Table 12 and Table 13 of the clinical study report (page
`100-101).
`
`Bioequivalence was determined based on comparison of the AUCs (AUCo4 & AUCM)
`between the Test product and the Listed Drug. The results are presented in the table
`below. Four (4) populations were evaluated using both reference scaled approach and the
`average BE approach. The results support bioequivalence.
`
`Table 344. Primary PKE Population Bioequivalence (FDA Requested and Eagle Proposed) and Secondary
`Sensitivity PKE Population (FDA Requested and Eagle Proposed) ANOVA Analysis Results for Eagle-
`BDM and Teva-BDM in “End-of-Life” Cancer Patients
`
`nnM mom-sum
`PKE Population
`
`Eagle-BDM (Tcsl)'
`cha-BDM (Referenccf
`Test/Reference‘
`90% Confidence Interval
`
`Primary PKE
`(N=60)
`
`9546.49
`
`9450.25
`
`Secondary
`Sensitivity PIG
`(N'57)
`9855.58
`
`961 8.32
`
`
`
`

`

`Eagle Pharmaceuticals, Inc.
`
`QUALITY ASSSSlVIENT
`Bendeka (bendamustine hydrochloride) injection
`
`PKE Population
`
`Secondary
`Primary PKE
`Secondary
`Primary PKE
`(N=60)
`Sensitivity PKE
`(N=t4)
`Sensitivity PKE
`
`(N=57)
`(N=38)
`
`hagIc-BIB'I ( l «:51!’
`9547.23
`9884.51
`8879.01
`9173.01
`
`ism-BDM (Referench
`‘
`9464.6
`9632.81
`8943.95
`9063.77
`Test/Referenre'
`1.01
`1.03
`0.99
`1.02
`
`90% Confidence Interval
`
`0.915 -1.115
`
`0.926 -1.137
`
`0.888 — 1.112
`
`0.899— 1.146
`
`
`
`
`
`
`
`
`
`llppcr (‘n'iical Bound
`S“
`
`$3“R
`BE Method
`131-: Result
`
`-().()9
`0.39!
`
`0.153
`RSABE
`Passed
`
`.
`‘
`.
`
`-().(I9
`0.39]
`
`0.153
`RSABE
`Passed
`
`-().()8
`0.383
`
`0.147
`RSABE
`Passed
`
`-0.()9
`0.402
`
`0.162
`RSABE
`Passed
`
`' Geometric Means Values
`
`PKparameters by-sex comparison was conducted on the Eagle proposed secondary
`population (n=3 8). The results indicated that females appeared to have higher Cmax and
`AUC than males, and the difference between female and male AUCs were higher for
`Teva-BDM than Eagle-BDM (18% vs 11%). The applicant indicated the differences are
`not clinically significant and there is no sex impact.
`
`Reviewer’s Assessment:
`
`The objective of Study EGL-BDM-C—l301 was to demonstrate that the EAGLE-BDM
`product given over a 10 min infusion interval is bioequivalent to the reference product
`(Teva—BDM) given over 60 min, and they have similar safety profiles (see Clinical safety
`review in DARRTS). Based on FDA recommendations given in a meeting held on
`l/15/2013, BE was based only on the AUCs for BDM, because the proposed product was
`intentionally formulated to exhibit different Cmax and Tmax compared to the Listed
`Drug (due to the difference in concentration and duration of administration).
`
`ABE analysis.
`
`The study design is acceptable. The RSABE method is deemed appropriate to assess BE
`by FDA for highly-variable drugs such as BDM HCl. The results showed the Eagle-BDM
`is bioequivalent to Teva-BDM for BDM AUCo4 and AUC“, for the 2 Primary PKE
`populations (FDA requested [n=60] and Eagle proposed [n=44]), as well as for the 2
`Secondary Sensitivity populations (FDA requested [n=57] and Eagle proposed [n=38]),
`respectively, by using the RSABE method as well as the unscaled— ABE method.
`
`This Biopharmaceutics Reviewer analyzed the provided raw PK data on the FDA
`recommended primary and secondary PKE populations only using the NCA, ABE, and
`RSABE tools of Phoenix Winnonlin 6.4. The results are summarized in the Table below.
`
`The results confirm that the drug product is highly variable (cv%=39%), and the
`proposed drug product is bioequivalent to the reference product by RSABE as well as
`
`

`

`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`Eagle Pharmaceuticals, Inc.
`
`
`
`--...... PME-
`
`M—
`
`—EE_—I‘Ii_
`[rm-mm—
`m
`RSABEm
`
`Em—IIE-IIE-IIE-
`
`the Eagle-BDM product.
`
`In addition to the parent drug BDM, the applicant also measured the metabolite M3 in the
`BE study but did not analyze the data. This is acceptable. According to Guidance for
`Industry Bioavailability and Bioequivalence Studies Submitted in NDAs or DVDS-
`GeneraI Considerations (Alarch 2014), measurement of the active ingredient, rather than
`metabolites is generally recommended. For this particular drug product, the parent drug
`BDM is in much higher quantity and the cytotoxic activity is primarily due to BDM,
`therefore BE evaluation was based on the parent drug BDM.
`
`The applicant’s conclusion of no gender efl'ect is consistent with the labeling of Treanda.
`
`The safety profiles ofthe two products are similar, despite the higher Cmax achieved by
`
`OVERALL ASSESSNIENT AND SIGNATURES:
`
`BIOPHARMACUETICS
`
`
`
`

`

`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`
`Eagle Pharmaceuticals, Inc.
`
`ASSESSMENT OF NHCROBIOLOGY
`
`35. Are the tests and proposed acceptance c1iteria for microbial bru‘den adequate for
`assuring the microbial quality of the drug product?
`
`Applicant’s Response: This can be adopted from the QbR—QOS and Module 3 provided
`from the firm.
`
`Reviewer’s Assessment:
`
`Product uali Microbiolo Assessment
`
`DRUG PRODUCT
`
`1.
`
`REVIEW OF COMlVION TECHNICAL DOCUNIENT—
`
`QUALITY (CTD-Q) MODULE 3.2: BODY OF DATA
`
`DRUG SUBSTANCE — Non-sterile
`
`S
`
`P
`
`

`

`I'MH
`
`QUALITY ASSSSMENT
`: Em deka (bendamustine hydrochloride) injectio;
`Eagle Pharmaceuticals, Inc.
`7
`
`Theproduct is labeled malti-dose with maximum of2 doses available
`in each vial.
`
`Description of the Composition of the Drug Product
`0 Description of drug product — Bendamustine hydrochloride injection is
`a sterile non-aqueous solution that is intended for infusion afier
`dilution in an IV solution. As stated in the Remarks Section, Drug
`product composition — The Batch Formula is presented in Table I
`(copied from Table 3.2.P.1-1)
`
`
`Table 1. Composition of Bendamustine HCl Injection, ‘25 mg/mL
`{
`Concentration
`
`25 mg/mL
`
`Active Ingredient
`
`WWW
`WW
`
`mm
`
`P.2.5 Microbiolo 1 'cal Attributes
`
`Description of container closure system — The container closure
`system used for the dru
`roduct consist of a 5 mL USP T
`I
`molded glass vial
`rubber stopper (DMF
`packa '
`for the vials 1s a sm e v1
`
`flip off seal. The secondary
`carton. The CCI information in
`
`DMF& was found adequate.
`
`P.2
`
`Pharmaceutical Development
`
`

`

`QUALITY ASSSSNIENT
`Bendeka (bendamustine hydrochloride) injection
`Eagle Pharmaceuticals, Inc.
`
`Reviewer’s Assessment: The product does not contain any materials sourced from
`
`38. If any of the materials used for the manufacture of the drug substance or drug
`product are of biological origin or derived from biological sources, what drug
`substance/drug product processing steps assure microbiological (viral) safety of
`the component(s) and how are the Viral inactivation/clearance capacity of these
`processes validated?
`
`Applicant’s Response: This can be adopted fiom the QbR—QOS and Module 3 provided
`from the firm.
`
`Reviewer’s Assessment: N/A
`
`
`
`OVERALL ASSESSMENT AND SIGNATURES: NIICROBIOLOGY
`
`
`
`