CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`207620Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`Product Quality Recommendation: APPROVAL
`
`NDA 207620
`
`Review # 01 Addendum
`
`Review Date: June 30, 2015
`
`Drug Name/Dosage Form Entresto (sacubitn'l and valsartan) Tablets
`
`Strength
`
`24 mg sacubitril and 26 mg valsartan
`49 mg sacubitril and 51 mg valsartan
`97 mg sacubitril and 103 mg valsartan
`
`Route of Administration
`
`Rx/OTC Dispensed
`
`Rx
`
`Applicant
`
`Novartis Pharmaceuticals Corporation
`
`US agent, if applicable
`
`N/A
`
`
`Raanan Bloom Q-g
`
`SUBMISSION(S) REVIEWED
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`Amendment
`
`DOCUMENT DATE
`
`25-JUN-2015
`
`26—JUN—20 l 5
`
`1 5-JUN-20 1 5
`
`ll—JUN-2015
`
`04 JUN-2015
`
`02—JUN-2015
`
`26-MAY-2015
`
`15-MAY—2015
`
`15-MAY-2015
`
`DISCIPLINE
`
`Drug Substance
`
`Drug Product
`
`Quali Review Team
`REVIEWER
`
`Anamitro Banerjee
`Sherita McLamore-Hines
`
`Bogdan Kurtyka
`
`Microbiology
`
`Robert Mello
`
`Facility
`
`Biopharmaceutics
`
`Zhong Li
`
`Salaheldin Hamed
`
`BRANCH/DIVISION
`
`ONDP Branch III/Division I
`
`ONDP Branch I/Division I
`
`OPF Branch l/Division of
`Process Assessment I
`OPF Branch /Division of
`
`Microbiolo¢ Assessment
`OPF Branch /Division of
`Ins ectional Assessment
`ONDP Branch III/Division of
`Bio harmaceutics
`
`Proj ect/Business Process Manager
`
`Maryam Kord Bacheh
`
`OPRO Branch I/Division I
`
`Application Technical Lead
`
`Wendy Wilson-Lee
`
`ONDP Branch I [Division I
`
`Laboratory (OTR)
`ORA Lead
`
`Karen D’Orzio
`
`Environmental Assessment (EA)
`
`ooNDP EA Team
`
`

`

`QUALITY REVIEW
`
`Table of Contents
`
`Table of Contents .......................................................................................... 2
`
`Quality Review Data Sheet .......................................................................... 3
`
`Executive Summary ...................................................................................... 4
`
`Addendum to Primary Quality Review....................................................... 9
`
`List of Deficiencies To Be Communicated.................................................. 12
`
`Attachments .................................................................................................. 13
`
`

`

`QUALITY REVIEW
`
`Quality Review Data Sheet
`
`1. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`2. RELATED/SUPPORTING DOCUNIENTS:
`
`A. DNIFs:
`
`TYPE HOLDER
`
`ITEM
`REFERENCED
`
`STATUS‘
`
`23902 TypeII
`
`Novartis
`Pharmaceutical
`
`Corporation
`
`Valsartan
`
`
`
`COMNIENTS
`
`REVIEW
`DATE
`
`25-NOV-2014
`
`lAdequate, 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
`
`DESCRIPTION
`
`failure
`
`104628
`
`LCZ696 (sacubitril/valsar’tan) for heart failure and chronic heart
`
`3. CONSULTS:
`
`No consults requested.
`
`

`

`QUALITY REVIEW
`
`1.
`
`Recommendations
`
`Executive Summary
`
`A. Recommendation and Conclusion on Approvability
`
`We recommend approval of NBA 207620 from a product gualig perspective for
`EntrestoTM (sacubitril/valsaitan) Tablets, 97/ 103, 49/51, and 24/26 mg when stored in the
`intended packaging and stored at USP Controlled Room Temperature.
`
`Additional 0P9 Langage for Action Letter
`
`The comparability protocols supporting post-approval changes to l) the drug product
`manufacturing site, control, batch size, and process and 2) the
`“(4) intermediate
`manufacturing site, control, batch size, and process are acceptable.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`Post-Marketing Commitment Subject to 506B: None
`
`Post—Marketing Agreements Not Subject to 506B: Development of a new dissolution
`method for all strengths with demonstrated discriminating ability,
`(m4)
`
`Using the new dissolution method and data from the overall multipoint
`dissolution profile from a minimum of 12 commercial batches per strength, manufactured
`under the same conditions as those used for the manufacture of the batches used in pivotal
`clinical
`trials,
`set
`the
`final
`dissolution
`acceptance
`criterion
`for EntrestoTM
`(sacubitril/valsartan) Tablets, 97/103, 49/51, and 24/26 mg.
`
`H.
`
`Summary of Quality Assessments
`
`(b) (4)
`
`A. Drug Substance [Sacubitril
`
`and Valsartan] Quality Summary
`
`1. Chemical Name or IUPAC Name/Structure
`
`Sacubitril: 4- { [(1 S,3R)- 1-([ 1 , l '-Biphenyl] -4-yhnethyl)-4-ethoxy-3 -methyl-4-
`oxobutyl]amino}-4—oxobutanoic acid
`Valsartan: N—Pentanoyl-N—{[2'-(1Htetrazol-5-yl)[ 1 , 1'-biphenyl]-4-yl]methy1}-L-valine
`
`2. Properties/CQAS Relevant to Drug Product Quality
`
`The CQAs relevagt
`
`to drug product thty are physical
`
`form, bulk density, and
`
`3. List of starting materials
`
`(I!) (4)
`
`

`

` QUALITY REVIEW
`
`4. Suppliers of starting materials (site)
`
`The quality of starting materials is controlled via the starting material specifications.
`These specifications are based on the expected, common routes of synthesis for the starting
`materials and provide for sourcing fi'om multiple suppliers.
`
`5. Summary of Synthesis
`
`Sacubitn'l
`the
`
`drug substance is synthesized— us1n
`starting maten .
`
`is s
`
`thesized in
`
`s
`
`thetic ste s
`
`startin
`
`from the
`
`
`
`6. Process
`
`The critical
`
`rocess ste s are the
`
`These rocess st
`
`s are considered critical due to their potential to im act
`Critical
`rocess
`arameters such as
`
`The
`
`rocess also includes in-process controls for
`Sacubitril
`
`the regulatory drug substances
`valsartan are designated as
`
`
`“valsartan include tests and acc
`under Novaitis’ quality system. However, the specifications for sacubitn'l
`
`strenfi, and quality ofthese compounds
`
`uri
`
`
`
`,
`
`tance criteria to control the identi
`
`7. Container Closure
`
`inc cennnencici cinccniceiecnneic—.
`
`8. Retest Period & Storage Conditions
`
`
`
`
`data provided in the
`Based on the stabili
`
`drug substance.
`is granted for sacubitril
`submission,
`
`
`
`ICH QlE, a I month re-test period is granted
`Based on the
`ta an in accor
`ce wr
`for the_ drug product m-process material.
`The recommended stora e
`
`condition for both drui substances and the in-process material
`
`isd
`
`-5-
`
`

`

`QUALITY REVIEW
`
`B. Drug Product [Sacubitril and Valsartan] Quality Summary
`
`1. Strength
`
`The drug product is available as a fixed dose combination of 24 mg sacubitril and 26 mg
`valsartan; 49 mg sacubitn'l and 51 mg valsartan; and 97 mg sacubitril and 103 mg valsartan
`
`2. Description/Commercial Image
`
`24 mg sacubiuil and 26 mg valsartan: violet white ovaloid biconvex film-coated tablet
`with beveled edges, unscored, debossed with “NVR” on one side and “LZ” on the other
`side; approximately 13.1 mm length and 5.2 mm width
`49 mg sacubitril and 51 mg valsaitan: pale yellow ovaloid biconvex film-coated tablet
`with beveled edges, unscored, debossed with “NVR” on one side and “L1” on the other
`side; approximately 13.1 mm length and 5.2 mm width
`97 mg sacubitril and 103 mg valsartan:
`light pink ovaloid biconvex film-coated tablet
`with beveled edges, unscored, debossed with “NVR” on one side and ‘I” on the other
`side; approximately 15.1 mm length and 6.0 mm width
`
`3. Summary of Product Design
`
`The tar et
`
`roduct was an oral, immediate-release dosa e form.
`
`
`
`Initial clinical studies
`
`4. List of Excipients:
`
`low substituted
`cellulose,
`Microcrystalline
`magnesium stearate, talc, colloidal silicon dioxide
`
`hydroxypropylcellulose,
`
`crospovidone,
`
`5. Process Selection (Unit Operations Summary)
`
`The manufactuiin
`
`rocess consists of
`
`ma'or unit 0 rations —_
`
`6. Container Closure
`
`
`valsartanl - 60-ct and 180-ct, 90 cc square, white, HDPE bottles with 38 mm,
`
`- induction sealed,,9 closures
`Commercial 97 m sacubl
`an 103
`square, white, HDPE bottles with 38 mm,
`closures
`
`valsartan — 60-ct, 90 cc and l80-ct, 175 cc
`induction sealed,_
`
`Ph ician’s Sam le all siren hs — 14 ct, 45 cc round, white, HDPE bottle with 28 mm,
`
`induction-sealed,
`closures
`
`
`Packs (all strengfl) — clear,
`
`, formed, blister pack with a
`
`-6-
`
`

`

`QUALITY REVIEW
`
`7. Expiration Date & Storage Conditions
`
`Based on the drug product stability information provided and in accordance with ICH
`QlE, we grant a 24 month drug product expiration date when stored at USP
`controlled room temperature, protected from moisture, in the intended container closure.
`
`8. List of co-packaged components
`
`There are no co-packaged components.
`
`C. Summary of Drug Product Intended Use
`
`Proprietary Name of the Drug Product
`
`Entresto
`
`Non Proprietary Name of the Drug Product
`
`Sacubitril and Valsartan
`
`Non Proprietary Name of the Drug Substances
`
`Sacubitril
`
`0)“) and Valsartan
`
`Proposed Indieation(s) including Intended Patient Population
`Duration of Treatment
`
`Treatment of Heart Failure
`Chronic
`
`Maximum Daily Dose
`
`97 mg sacubitril and 103 mg valsartan.
`
`administered twice daily Alternative Methods of Administration
`
`None identified
`
`D. Biopharmaceutics Considerations
`
`1. BCS Classification:
`
`0 Drug Substance: No BCS Classification proposed by the
`Applicant. The solubility is pH dependent.
`In 0.1 N HCL,
`solubility is 0.05 mg/mL and >50 mg/mL at pH 6.8. Absolute
`bioavailability of valsartan is 25%, but it is known to undergo
`significant first-pass metabolism. Most likely the permeability is
`high. The absolute bioavailability 60% for sacubitril. The BCS
`classification is BC S IV.
`
`0 Drug Product: Not Applicable
`
`2. Biowaivers/Biostudies
`
`0 Biowaiver Requests: Not Applicable
`
`0 PK studies: Bridging study for the 24/26 mg formulation
`-
`IVIVC : Not Applicable
`
`E. Novel Approaches
`
`(m4) two active ingredients
`The drug product contains
`— sacubitril and valsartan. Sacubitril is a new molecular entity. Valsartan is an approved
`drug substance.
`om) quickly hydrolyzes in vivo to release sacubitril and
`valsartan.
`m4)
`
`

`

` QUALITY REVIEW
`
`
`The dru substance control stIate
`
`relies on control of
`
`bioavailabili
`
`strength, quali
`to ensure the identity, purity,
`of sacubitril and valsartan. As agreed upon by the Agency,
`the aJulicant’s u
`.
`s
`tems and standards
`
`, and
`
`
`
`is granted to control the shelf-life of
`
`F. Any Special Product Quality Labeling Recommendations
`
`There are no special labeling recommendations form a product quality perspective.
`
`G. Process/Facility Quality Summary (see Attachment A)
`
`H. Life Cycle Knowledge Information (see Attachment B)
`
`MUWMML
`
`Wendy | ‘é’mimmm
`ouHil-ls,ou=FlJA,ou=People.
`0.923421920030alom.1=130
`Wilson 6233mm“
`
`For the OPQ Quality Review Team
`
`

`

`QUALITY ASSESSNIENT
`
`Product Quality Recommendation: Pending
`
`NDA 207620
`
`Review # 01
`
`Review Date: May 15, 2015
`
`Dru_ Name/Dosa_e Form Entresto (sacubitril and valsartan) Tablets
`Strength
`24 mg sacubitril and 26 mg valsartan
`49 mg sacubitril and 51 mg valsartan
`97 mg sacubitril and 103 mg valsartan
`—_
`—__
`
`15-APR-2015
`
`16-JAN-2015
`
`30-SEP-2014
`
`
`Raanan Bloom
`
`DISCIPLINE
`
`Drug Substance
`Drug Product
`
`Microbiology
`Facility
`Biopharmaceutics
`
`Project/Business Process
`Manager
`Application Technical Lead
`Laboratory (OTR)
`ORA Lead
`
`Environmental Assessment (EA)
`
`Quali Review Team
`
`Anamitro Banerjee
`Sherita McLamore—Hines
`
`Bogdan Kuflyka
`Robert Mello
`
`Zhong Li
`Salaheldin Hamed
`
`Olga Simakova
`
`BRANCH/DIVISION
`ONDP Branch III/Division I
`ONDP Branch I/Division I
`OPF Branch 1/Division
`OPF Branch /Division of
`OPF Branch /Division of
`ONDP Branch HI/Division of
`
`Biophannaceutics
`OPRO Branch I/Division I
`
`Wendy Wilson-Lee
`
`ONDP Branch I /Division I
`
`Karen D’Oizio
`
`

`

`QUALITY REVIEW
`
`Table of Contents
`
`Table of Contents .......................................................................................... 2
`
`Quality Review Data Sheet .......................................................................... 3
`
`Executive Summary ...................................................................................... 4
`
`Primary Quality Review............................................................................... 9
`
`ASSESSMENT OF THE DRUG SUBSTANCE ............................................................... 9
`
`2.3.S
`
`DRUG SUBSTANCE .............................................................................. 9
`
`S. l .3 General Properties ..................................................................................... 9
`
`ASSESSMENT OF THE DRUG PRODUCT .................................................................. 27
`
`2.3.P
`
`DRUG PRODUCT ................................................................................. 27
`
`R2
`
`Comparability Protocols ......................................................................... 58
`
`ASSESSMENT OF THE PROCESS ................................................................................ 60
`
`2.3.P
`
`DRUG PRODUCT ................................................................................. 60
`
`R2
`
`Comparability Protocols ......................................................................... 85
`
`ASSESSMENT OF THE FACILITIES ............................................................................ 89
`
`2.3.S
`2.3.P
`
`DRUG SUBSTANCE ............................................................................ 89
`DRUG PRODUCT ................................................................................. 92
`
`ASSESSMENT OF THE BIOPHARMACUETICS ........................................................ 95
`
`ASSESSMENT OF MICROBIOLOGY ......................................................................... 112
`
`A
`
`APPENDICES ................................................................................................... 1 13
`
`A2
`
`Adventitious Agents Safety Evaluation ............................................... 113
`
`ASSESSMENT OF ENVIRONMENTAL ANALYSIS ................................................ 114
`
`I.
`
`Review of Common Technical Document-Quality (Ctd-Q) Module 1 .............. 115
`
`Labeling & Package Insert .............................................................................................. 115
`
`11.
`
`III.
`
`List of Deficiencies To Be Communicated ......................................................... 115
`
`Attachments ........................................................................................................ 1 16
`
`

`

`QUALITY REVIEW
`
`Quality Review Data Sheet
`
`1. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`2. RELATED/SUPPORTING DOCUNIENTS:
`
`A. DMFs:
`
`TYPE
`
`ITEM
`HOLDER REFERENCED STATUSl
`
`23902
`
`Type II
`
`
`
`DATE
`REVIEW
`COMPLETED
`
`25-Nov-2014
`
`COMMENTS
`
`Valsartan
`
`1
`
`Novartis
`Pharmaceu
`tical
`
`Corporatio
`n
`
`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
`104628
`
`failure
`
`DESCRIPTION
`LCZ696 (sacubitril/valsartan) for heart failure and chronic heart
`
`3. CONSULTS:
`
`No consults requested.
`
`

`

`QUALITY REVIEW
`
`1.
`
`Recommendations
`
`Executive Summary
`
`A. Recommendation and Conclusion on Approvability
`
`The overall product quality recommendation is pending due to the following outstanding
`items:
`
`1. Completion of facilities inspections and evaluations
`2. Submission of revised carton and container labels
`3. Submission of confirmatory stability data for the drug product and
`
`M“)
`
`4. Submission of a revised dissolution specification
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`
`and/or Risk Management Steps, if Approvable
`
`The comparability protocols supporting post-approval changes to 1) the drug product
`manufacturing site, control, batch size, and process and 2) the
`M“) intermediate
`manufacturing site, control, batch size, and process are acceptable.
`
`H.
`
`Summary of Quality Assessments
`
`A. Drug Substance [Sacubitril
`
`(m4) and Valsartan] Quality Summary
`
`1. Chemical Name or IUPAC Name/Structure
`
`Sacubitril: 4- { [(1 S,3R)— l —([ l , l '—Biphenyl]-4—ylmethyl)—4-ethoxy—3 —methyl-4—
`oxobutyl]amino}—4—oxobutanoic acid
`Valsartan: N-Pentanoyl-N- {[2'-(1Htetrazol—5-yl)[l , 1'-biphenyl]-4-yl]methyl} -L-valine
`
`2. Properties/CQAs Relevant to Drug Product Quality
`
`The CQAs relevgrg to drug product quality are physical form, bulk density, and
`)
`
`3. List of starting materials
`
`(I!) (4)
`
`4. Suppliers of starting materials (site)
`
`The quality of starting materials is controlled via the starting material specifications.
`These specifications are based on the expected, common routes of synthesis for the
`starting materials and provide for sourcing from multiple suppliers.
`
`

`

` QUALITY REVIEW
`
`5. Summary of Synthesis
`
`
`Sacubitn'l
`
`
`using the
`
`drug substance is synthesized—
`starting material.
`
`is s
`
`thesized in
`
`6. Process
`
`The critical
`
`rocess ste s are the
`
`These rocess ste s are considered critical due to their potential to '
`. Critical
`rocess arameters such as
`
`Sacubitril
`
`
`
`
`under Novartis’ quality system. However, the specifications for sacubitril
`and valsartan include tests and acceptance criteria to contIol the identi
`, uri
`,
`
`
`
`
`strenfi, and inalii of these compounds
`
`7. Container Closure
`
`The commercial drug substance container closure is—
`
`8. Retest Period & Storage Conditions
`
`
`
`Based on the stability data provided in the
`submission,
`is granted for sacubitIil - drug
`
`substance. Based on the data and in accordance with ICH QlE, a .month re-test period
`is granted for them drug product in—process material. The recommended
`storaie condition
`i substances and the in-process material is—
`
`or ot
`
`B. Drug Product [Sacubitril and Valsartan] Quality Summary
`
`

`

` QUALITY REVIEW
`
`1. Strength
`
`The drug product is available as a fixed dose combination of 24 mg sacubitril and 26 mg
`valsartan; 49 mg sacubitril and 51 mg valsartan; and 97 mg sacubitlil and 103 mg
`valsartan
`
`2. Description/Commercial Image
`
`24 mg sacubitlil and 26 mg valsartan: violet white ovaloid biconvex film-coated tablet
`with beveled edges, unscored, debossed with “NVR” on one side and “LZ” on the other
`side; approximately 13.1 mm length and 5.2 mm width
`49 n_1g sacubitril and 51 n_1g valsartan: pale yellow ovaloid biconvex film-coated tablet
`with beveled edges, unscored, debossed with “NVR” on one side and “L1” on the other
`side; approximately 13.1 mm length and 5.2 mm width
`97 mg sacubitril and 103 mg valsartan:
`light pink ovaloid biconvex film-coated tablet
`with beveled edges, unscored, debossed with “NVR” on one side and ‘I” on the other
`side; approximately 15.1 mm length and 6.0 mm width
`
`3. Summary of Product Design
`
`roduct was an oral, immediate-release dosa e form.
`
`Initial clinical studies
`
`The tar et
`
`
`
`4. List of Excipients:
`
`low substituted hydroxypropylcellulose,
`Microcrystalline cellulose,
`magnesium stearate, talc, colloidal silicon dioxide
`
`crospovidone,
`
`5. Process Selection (Unit Operations Summary)
`
`The manufacturin
`
`rocess consists of
`
`ma'or unit 0 erations —
`
`6. Container Closure
`
`Commercial 24 m sacubitril and 26 m valsartan' 49 m sacubitril and 51
`
`valsartan! — 60-ct and 180-ct, 90 cc
`
`-, induction sealed,flfildsmes
`
`, white, HDPE bottles with 38 mm,
`
`sacubitn'l and 103 m valsartan — 60-ct, 90 cc and l80-ct, 175 cc
`Commercial 97
`square, white, HDPE bottles with 38 mm,
`induction sealed,_
`closures
`
`Ph ician’s Sam 1e all stren
`induction-sealed,
`
`— 14 ct, 45 cc round, white, HDPE bottle with 28 mm,
`closures
`
`

`

`QUALITY REVIEW
`
`M“) Packs all stren hs — clear,
`a push through, aluminum foil blister lidding
`
`m", formed, blister pack with
`
`7. Expiration Date & Storage Conditions
`
`Based on the drug product stability information provided in the submission and in
`accordance with ICH QlE, we grant a 24 month drug product expiration date when
`stored at controlled room temperature, protected from moisture, in the intended container
`closure.
`
`8. List of co-packaged components
`
`There are no co-packaged components.
`
`C. Summary of Drug Product Intended Use
`
`Pmmm Namemmnmgrr
`
`Non Proprietary Name of the Drug Product
`
`Sacubitfil and Valsartan
`
`Non Proprietary Name of the Drug Substance
`
`Sacubitfil
`Valsartan
`
`Proposed Indication(s) including Intended
`Patient Po . nlation
`
`Treatment of Heart Failure
`
`None identified
`
`Maximum Daily Dose
`
`Alternative Methods of Administration
`
`Chronic
`
`97 mg sacubitril and 103 mg valsartan,
`administered twice daily
`
`D. Biopharmaceutics Considerations
`
`1. BC S Classification:
`
`0 Drug Substance: No BCS Classification proposed by the
`Applicant. The solubility is pH dependent. In 0.1 N HCL,
`solubility is 0.05 mg/mL and >50 mg/mL at pH 6.8. Absolute
`bioavailability of valsartan is 25%, but it is known to undergo
`significant first-pass metabolism. Most likely the permeability is
`high. The absolute bioavailability 60% for sacubitlil. The BCS
`classification is BCS IV.
`
`0 Drug Product: Not Applicable
`
`2. Biowaivers/Biostudies
`
`o Biowaiver Requests: Not Applicable
`
`PK studies: Bridging study for the 50 mg formulation
`IVIVC : Not Applicable
`
`E. Novel Approaches
`
`

`

`"""‘""‘
`m
`
`
`
`QUALITY REVIEW
`
`"”"“
`
`
`The drug prom contains— two We
`ingredients — sacubitlil and valsartan. Sacubitril is a new molecular entity. Valsartan is
`an approved drug substance.
`'ckl h drol
`es in vivo to release
`
`
`sacubitril and valsartan.
`
`
`
`
`The dru substance control strate
`
`relies on control of
`
`to ensure the identity, purity, strength, quali
`
`, and
`
`of sacubitnl and valsartan. As agreed upon by the Agency,
`
`shelf-life of sacubitril
`
`F. Any Special Product Quality Labeling Recommendations
`
`There are no special labeling recommendations form a product quality perspective.
`
`G. Process/Facility Quality Summary (see Attachment A)
`
`H. Life Cycle Knowledge Information (see Attachment B)
`
`mgiulysigmmml
`
`Wendyl fisswmm
`092342.19momom.1=130
`Wilson —S mngw
`
`

`

`""‘""5
`m;
`
`QUALITY REVIEW
`
`"'M'“
`a..-..._....
`
`ASSESSMENT OF THE BIOPHARMACUETICS
`
`27. Are the in-vitro dissolution test and acceptance criteria adequate for assuring
`consistent bioavailability of the drug product?
`
`LCZ696 film-coated tablets (FCT) are desified as a combination ofsacubitril (AHU377,
`
`(the drug substance)
`a new molecular entity) and valsartan
`is a salt complex comprising LCZ696 (Sacubitn'Walsaitan anionic moieties), sodium
`cations, and water molecules. LCZ696 has been formulated as 50 mg (24.3 mg/24.7 mg),
`100 mg (48.6 mg/51.4 mg), 200 mg (97.2 mg/102.8 mg) immediate release film-coated
`tablets for oral administration. Following oral administration, LCZ696 dissociates into
`two components, valsartan and the pro-drug sacubitril (AHU377); the latter is further
`
`metabolizedto the neiriliin inhibitor LBi657. The 200 mi and the 100 mi tablets are
`
`DISSOLUTION METHOD
`
`The proposed dissolution method is summarized in table 1:
`
`Table 1. Pro 1 osed Dissolution Method and Acce - tance Criterion.
`
`mm“— USP II
`
`50 rpm 900 mL
`
`Phosphate
`Buffer, pH
`6.8
`
`HPLC/UV
`7L=255 nm
`
`The Applicant proposed the use of apparatus II with paddles for dissolution testing
`because it is considered a standard apparatus. The Applicant provided data to justify the
`selection of the dissolution medium pH. The proposed pH is based on the solubility
`profile of valsartan and sacubitril, both of which exhibit high solubility at pH higher than
`5.0 and low solubility at acidic pH (figure 1). Therefore, the Applicant chose pH 6.8 for
`h siolo ' cal relevance.
`
`
`
`METHOD DISCRIMINATING ABILITY
`
`-95-—
`
`

`

`QUALITY REVIEW
`
`
`
`ACCEPTANCE CRITERION
`
`The applicant proposes Q = 5% for both sacubitril and valsartan at
`
`ssolution data for the registration batc es are provided
`three dosage strengths. The
`tables 2-4. The dissolution data do not support the proposed acceptance criteria.
`= %
`
`minutes for the
`
`atl minutes is likeli to result in an lmder-discriminating method,
`
`-99-
`
`

`

`QUALITY REVIEW
`
`
`
`

`

`QUALITY REVIEW
`
`Dissolution Method: ACCEPTABLE
`
`The applicant investigated the effect of medium pH on dissolution and provided data to
`support the selection ofpH 6.8. The selection ofthe remaining methodparameters (i. e.,
`apparatus, paddle speed, buffer type, etc.) were not supported. The selected method,
`however, is mild (i.e. 50 rpm and no surfactant), which provides more discriminating
`ability.
`
`Discriminating Ability of the Dissolution Method: ACCEPTABLE
`The applicant investigated the eflect of critical material attributes of drug substance
`@article size distribution) and the effect of tablet hardness, a critical quality attribute,
`on dissolution. The proposed dissolution method and acceptance criterion were not
`able to discriminate batches with parameters outside the target ranges. However, the
`discriminating ability of the method can be enhanced with tighter dissolution
`acceptance criteria.
`
`
`
`Acceptance Criterion: NOT ACCEPTABLE
`The applicant proposes Q = 8% at 8 minutes as the acceptance criterion for all
`dosage strengths. The provided data for the registration batches do not support the
`.
`.
`.
`(moo
`.
`(b)
`.
`om)
`proposed acceptance criterion, With
`A dissolved at (4) minutes
`The proposed acceptance criterion compromises the
`discriminating ability ofthe method,
`out).
`The applicant will be requested to change the acceptance criteria to Q = 23% at 25
`instead a the ro osed
`om).
`
`28. Are the changes in the formulation, manufacturing process, manufacturing sites
`during the development appropliately bridged to the commercial product?
`
`(It) (4)
`
`The coated 100 mg and 200 mg tablets
`used in the Phase 3 clinical trials were of the same component and composition as the To-
`be-marketed fonnulation. Therefore, no bioequivalence studies were performed. The 50
`mg formulation, however, was fluther developed during commercial scale 11p to the To-
`be-marketed fonnulation and a bioequivalence study (study LCZ696B2114) was
`conducted to ensure therapeutic equivalence.
`
`Design
`
`Methodology
`
`received CSF in period 1, FMI in period 2, and C SF in peliod 3.
`
`50 n1 LCZ696 clinical sen/ice fonn C SF in health volunteers
`
`A randomized, open—label, single—dose, two—treatment, two sequence,
`three- 0 eriod, re u licate cross-over
`
`Subjects were randomized into one of two sequences in a 1:1 ratio. In
`the first sequence (TRT), subjects received FMI in period 1, CSF in
`peliod 2, and FMI in period 3. In the second sequence (RTR), subjects
`
`-101-
`
`

`

`hummlmmm
`
`QUALITY REVIEW
`
`1 Mahatma-M
`
`Test product: LCZ696 50 mg FMI (Batch No. AEUS/2010—0432)
`Reference product: LCZ696 50 mg CSF (Batch No. H941CI)
`
`The study consisted of a screening period up to 28 days, a baseline
`evaluation prior to each treatment period, three single-dose treatment
`periods, and 2 washout periods that lasted from 7 to 14 days.
`
`Log-transformed PK parameters (AUC1m, AUCinf, and Cm) were
`analyzed for AHU377, LBQ657, and valsartan by linear—fixed effects
`model, with fonnulation, sequence, period, and subject as fixed
`factors. The analysis was carried out on the set of subjects with
`evaluable PK 1 arameters for at least one test and one reference 1 eriod.
`
`
`
`A total of 85 subjects (63 males and 22 females) were enrolled and
`randomized in the study. Four subjects were discontinued early from
`the study, one subject was withdrawn due to a protocol deviation, two
`subjects were lost to follow—up, and one subject was withdrawn as per
`the physician’s decision. Demographic summary of the patients
`recruited for the study is summarized in the following table :
`
`
`
`
`
`Sequence 1
`Sequence 2
`A" SUbiGCtS
`
`
`N=42
`"=43
`N=85
`
`Age (years)
`
`Mean (SD)
`Median
`
`39.5 (10.4)
`41.0
`
`41.0 (8.9)
`44.0
`
`40.3 (9.6)
`43.0
`
`Sex- n(%)
`
`Race - n(%)
`
`Ethnicity _ n(%)
`
`Weight (kg)
`
`Height (cm)
`
`BMI (kg/m2)
`
`Range
`Female
`Male
`Black
`Caucasian
`Hispanic or Latino
`Other
`Mean (SD)
`Median
`
`Range
`Mean (SD)
`Median
`
`Range
`Mean (SD)
`Median
`
`21 - 55
`10 (24%)
`32 (76%)
`9 (21%)
`33 (79%)
`40 (95%)
`2 (5%)
`75.5 (10.3)
`76.0
`
`57.0 — 94.1
`170.4 (8.2)
`172.3
`
`149.5 - 181.5
`26.0 (2.8)
`26.5
`
`19 - 54
`12 (28%)
`31 (72%)
`7 (16%)
`36 (84%)
`38 (88%)
`5 (12%)
`77.4 (11.3)
`74.7
`
`57.0 — 103.2
`170.2 (9.3)
`170.0
`
`153.5 - 190.5
`26.7 (2.6)
`26.7
`
`19-55
`22 (26%)
`63 (74%)
`16 (19%)
`69 (81%)
`78 (92%)
`7 (8%)
`76.5 (10.82)
`76.0
`
`57.0 — 103.2
`170.3 (8.7)
`170.0
`
`149.5 — 190.5
`26.3 (2.7)
`26.6
`
`
`
`Subjects/
`Demographics
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Results
`
` Summary of
`
`21.3 — 29.8
`19.7 — 29.9
`Range
`Sequence 1: LCZGSG 50mg FMI ll LCZ696 50mg CSF ll LC2696 50mg FMI
`S ouence 2: LCZ696 50m CSF II LCZ696 50m FMI I/ LCZ696 50m. CSF
`
`
`
`
`19.7 — 29.9
`
`Out of the recruited 85 subjects, Subject #1001002 did not meet the
`inclusion criteria; Subject #1001067 and Subject #1001074 completed
`only period 1; and Subject #1001069 completed period 1 and period 2
`of the study. In the study, the observed pre-dose valsartan
`concentrations were >5% of Cmax for subject #1001113 at all three
`treatment periods and for Subject #1001055 at period 1. Therefore,
`data from these subjects were excluded from the PK/statistics analysis
`according to the analysis plan.
`The PK parameters for AHU377 are summarized in the following
`
`-102—
`
`

`

`'““"‘
`IafiaaaaaLl
`
`QUALITY REVIEW
`
`'DAFH
`
`table:
`Formulations
`
`AUCInf
`
`AUClast
`
`CSF
`
`FMI
`
`(ng'hrImL)
`123
`547
`161
`170
`516
`1020
`29.5
`122
`547
`159
`120
`528
`993
`29.1
`
`(no‘hrImL)
`123
`544
`161
`168
`514
`1010
`29.6
`124
`541
`159
`117
`525
`989
`29.4
`
`Mean
`SD
`Min
`Median
`Max
`CV96
`
`Mean
`SD
`Min
`Median
`Max
`CV96
`
`Cmax
`
`("91le
`123
`580
`333
`1 16
`499
`1650
`57.4
`124
`561
`287
`92.0
`51 1
`1850
`51 .1
`
`T1I2
`
`(hr)
`123
`0.990
`0.277
`0.552
`0.943
`2.09
`28.0
`122
`0.994
`0.239
`0.534
`0.948
`2.10
`24.0
`
`Tmax
`
`(hr)
`123
`-
`-
`0.333
`0.333
`3.00
`-
`124
`-
`-
`0.333
`0.533
`4.00
`-
`
`The AHU377 Mean PK profiles are shown in the following figure:
`
`E
`g 800
`5
`E 600
`
`0 400
`g
`g
`E 200
`
`5 o
`
`-O- FMI
`—v— CSF
`
`t m
`
`E
`‘2 100
`8
`g m
`
`1
`
`0
`E
`8
`E 0.1
`
`
`.
`w— o
`.
`2
`4
`5
`3
`1°
`
`0
`12
`
`o
`
`§ 0‘"
`
`0
`
`2
`
`4
`
`0
`
`0
`
`10
`
`12
`
`Time (hr)
`1]". (m
`The PK parameters for LBQ657 are summarized in the following
`table:
`Tablets
`
`Cmax
`
`T1l2
`
`AUCinf
`
`AUCIast
`
`CSF
`
`FMI
`
`N
`Mean
`SD
`Min
`Median
`Max
`CV96
`N
`Mean
`SD
`Min
`Median
`Max
`CV96
`
`(ng‘hrlmL)
`123
`24200
`7140
`8960
`23400
`59400
`29.5
`124
`23300
`6210
`6450
`22600
`57400
`26.6
`
`(ng‘hrImL)
`123
`23600
`6910
`8590
`22700
`57300
`29.3
`124
`22800
`6080
`5980
`22000
`56100
`26.7
`
`(nglmL)
`123
`2220
`505
`822
`2140
`4130
`22.8
`124
`2180
`482
`497
`2180
`4240
`22.1
`
`(hr)
`123
`10.2
`2.59
`6.56
`9.43
`18.5
`25.3
`124
`10.1
`2.28
`6.68
`9.53
`19.6
`22.7
`
`
`The mean LBQ657 PK profiles are shown in the following figure:
`
`—103—
`
`Tmax
`
`(hr)
`123
`-
`-
`1 .00
`2.00
`4.00
`-
`124
`-
`-
`1 .00
`2.00
`6.00
`-
`
`

`

`QUALITY REVIEW
`
`
`
`
`
`LBQWPlum:Concentrations(nglmL) 8
`
`gS
`
`4)
`
`Time (ht)
`
`
`
`
`
`
`
`L806”Plum:Concemmlom(ngImL) §
`
`..fl
`
`
`
`40
`
`Time (hr)
`
`The PK parameters for valsartan are summarized in the following
`table:
`Tablets
`
`AUCInf
`
`AUCIast
`
`Cmax
`
`T1I2
`
`Tmax
`
`(hr)
`120
`
`(ng‘hrImL)
`1 18
`7300
`2740
`2010
`6890
`18000
`37.6
`123
`7030
`2480
`2210
`6840
`15400
`35.3
`
`(ng'htImL)
`120
`7130
`2720
`1890
`6760
`17700
`38.2
`123
`6890
`2480
`1830
`6700
`15300
`36.0
`
`Max
`CV96
`
`(ngImL)
`120
`1 190
`463
`288
`1 120
`3680
`39.0
`123
`1 160
`455
`315
`1080
`2680
`39.1
`
`(hr)
`1 18
`6.1 1
`4.27
`3.34
`5.43
`48.6
`69.9
`123
`5.76
`1 .83
`3.68
`5.38
`20.4
`31.7
`
`The mean valsartan PK profiles are shown in the following figure
`mm
`
`
`
`
`
`
`
`VllnrtanPlum-Concentrations(nglmL)
`
`1“
`
`14m
`
`12m
`
`10m
`
`4)
`
`Time (hr)
`
`
`
`
`
`VlbamnPlumConcentrluonl(ngImL)
`
`..
`
`.0..—oO
`
`20
`
`40
`
`60
`
`Time (II)
`
`The statistical analysis of the PK parameters is summarized in the
`followin 7 table:
`
`-104-
`
`

`

`QUALITY REVIEW
`
`
`Parameter
`”my“ [Unit]
`
`Treatment N
`
`Adjusted
`geometric
`mean "
`
`90% CI for
`Ratio
`(TestIReference, %)* ratio (7.)“
`
`AHU377 AUOnflng'N/HIL) Test
`Refaence
`
`120 514.23
`123 526.62
`
`AUCIast
`(ng‘rrlmL)
`
`TS,
`
`122 510.70
`123 524.50
`
`97.65
`
`.
`
`[94.97,100.41]
`
`[94.02. 100.23]
`
`[86.61.106.80]
`.
`122 485.52
`Omax(nglmL)
`
`123 504.82
`
`LBQGS7 AUCinf(ng"hrImL)
`
`AUClaSl
`(ng‘l‘rlmL)
`
`0max(rlglmL)
`
`AUCint(ng'trImL)
`
`AUClast
`(ng‘mmL)
`
`Cmax(nglmL)
`
`122 2277402
`123 2305301
`
`122 2212.25
`
`123 22470 74
`
`122 2134.68
`123 2140.84
`
`121 6551.66
`118 6851.74
`
`121 6396.96
`
`120 6664.36
`
`121 1070.45
`120 111766
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`[97.61.9999]
`
`[97.63 . 100.08]
`
`[97.35.102.14]
`
`[90.13 _ 101.45]
`
`[90.05 , 101.70]
`
`[89.46.102.50]
`
`
`
`The safety evaluation included all subjects who received at least one
`dose of the study drug. A total of 18 adverse events were reported in
`15 subjects (17.6%) during the study. No deaths or severe adverse
`events occurred after randomization. Most AEs were not suspected to
`be related to the study medication. Only three AEs (Subject #1001064;
`headache, and Subjects #100116 and #1001156; dizziness) were
`suspected to be related to the study drug by the study investigator. All
`AEs were mild in intensity, and most ofien resolved within the
`duration of the study without any treatment. None of the AEs led to
`the discontinuation of any of the subjects.
`
`Summary of
`Safety
`
`The applicant provides a detailed method validation report of the bioanalytical method
`for the sacubitril pro-drug (AHU377), active metabolite (BLQ657), and valsartan. The
`validation report
`investigated the specificity, absolute recovery and matrix efl'ects,
`carryover, calibration, intra— and inter-day accuracy and precision, linearity, and stability.
`The reported results met the acceptance criteria outlined by the bioanal