CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`210259Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`Recommendation: APPROVAL
`
`NDA 210259
`
`Review #1
`
`Dru Name/Dosa {e Form
`StIen I
`
`Route of Administration
`
`Rx/OTC Dispensed
`A licant
`
`US a cut, ifae elicable
`
`Acalabrutinib Ca 0 sules
`100 me
`
`Acerta Phalma B.V.
`
`REVIEWED
`
`Amendment SD 0015
`
`Amendment SD 0017
`Amendment SD 0018
`
`DATE
`
`13-Jun-17
`
`25-Au-17
`
`25-Au-17
`
`30—Au —17
`os-Set-17
`
`DS, DP
`
`
`Anamitro Baner'ee
`
`DISCIPLINE
`
`Quali Review Team
`PRIMARY REVIEWER SECONDARY REVIEWER
`
`Drug Master File/Drug
`Substance
`
`Linsey Saunders and
`Paresma Patel
`
`Anamitro Banerjee
`
`Dru Product
`
`Microbiolo 3
`Facili
`
`Bio harmaceutics
`
`Regulatory Business
`Process Mana {er
`A ulication Technical Lead
`
`Laborato OTR
`
`Environmental
`
`0 1amrul Ma'mnder
`
`S
`
`Ruth Moore
`
`Yan- Zhao
`
`Rabiya Laiq
`
`Sherita McLamore
`
`S
`
`Ra'iv A . arwal
`
`Rakhi Shah
`Ea:
`Zhihao Peter 0 iu
`
`O onanabofa Eradili
`
`n/
`
`E:
`
`S
`
`OPQ-XOPQ—TEM-0001v04
`
`Page 1 of 1
`
`Effective Date: 14 February 2017
`
`

`

`
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`
`Item Referenced
`
`0’)(
`
`a
`
`Date Rev1ew Comments
`Com I leted
`No Review
`
`Adequate
`information
`
`
`
`No Review
`
`No Review
`
`No Review
`
`No Review
`
`No Review
`
`No Renew
`
`No Review
`
`No Review
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`Adequate
`information
`
`provided in the
`NDA
`
`B. Other Documents: IND, RLD, or sister a
`
`licalions
`
`DOCUMENT
`
`_ 118717 —
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`2. CONSULTS
`
`N/A
`
`OPQ-XOPQ—TEM-0001V04
`
`Page 1 of 1
`
`Effective Date: 14 February 2017
`
`

`

`
`
`Executive Summary
`
`1.
`
`Recommendations and Conclusion on Approvability
`
`OPQ recommends APPROVAL of NDA 210259 for Calquence (acalabrutinib) capsules,
`100 mg. As part of this action, OPQ grants a 8—month re-test period for the drug
`substance when stored at or below 8°C, and a 24-month drug product expiration period
`when stored at stored at controlled room temperature (25°C/60% RH). There are no
`outstanding issues and no post-approval quality agreements to be conveyed to the
`applicant.
`
`II.
`
`Summary of Quality Assessments
`
`A. Product Overview
`
`NDA 210259 was submitted for Calquence (acalabrutinib) capsules, 100 mg in
`accordance with section 505(b)(1) of the Food, Drug and Cosmetic Act. Acalabrutinib is
`an orally bioavailable, Bruton tyrosine kinase inhibitor OBTK) indicated for patients with
`mantle cell lymphoma GVICL) who have received at least one prior therapy. Acalabrutinib
`is an Nh/IE which was originally investigated under IND 118717 and received orphan
`designation in September 2015.
`
`Acalabrutinib is a small chiral molecule that is manufactured as a single enantiomer (S)
`in a linear manner. Acalabrutinib is a BCS class 2 compound that exhibits BCS class 1
`characteristics under in vivo conditions. The drug product, Calquence (acalabrutinib)
`capsules, 100 mg, is presented as a
`(mo hard gelatin capsule, with a blue cap and yellow
`body, printed with ‘ACA 100mg’ in black ink and containing 100 mg of acalabrutinib,
`microcrystalline cellulose, pregelatinized starteh, sodium starch glycolate and magnesium
`stearate.
`
`The dosing regimen for Calquence (acalabrutinib) capsules is 100 mg orally twice daily.
`
`Based on the information provided in this application (original submission and in
`responses to information requests), OPQ considers all review issues adequately addressed
`and potential risks to patient safety, product efficacy, and product quality mitigated
`appropriately. Accordingly, OPQ recommends APPROVAL ofNDA 210259 and grants
`a_ (3-month re-test eriod for the dru substance and a 24 month ex iration eriod for the
`drug product when stored at ICH controlled room temperature in the commercial
`pa kagm'g.
`
`Proposed Indication(s) including
`Intended Patient Population
`
`Indicated for the treatment of patients with mantle cell
`lymphoma OVICL) who have received at least one prior
`thera
`
`
`
`Duration of Treatment
`
`ID
`
`ation of treatment is until disease progression or
`acce table toxici
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 1 of 7
`
`Effective Date: 14 February 2017
`
`

`

`
`
`
`
`
`
`Effective Date: 14 Februaly 2017
`
`B. Quali Assessment Overview
`J‘7 L
`'HHIH m“;
`
`OPQ-XOPQ-TEM—0001v04
`
`Page 2 of 7
`
`

`

`QUALITY ASSESSMENT
`
`
`
`
`
`Co
`
`arab' '
`
`rotocol
`
`This application includes a comparability protocol in which AstraZeneca, Sweden
`would be added as an alternate site for drug product manufacture, QC and stability
`testing. The applicant proposedto submit this change in the form ofa CBE-30
`supplement. The applicant indicates that the addition ofthis alternative site will ensure
`security and contimrity of supply of the drug product. The comparability protocol was
`reviewed by the drug product, process and facility reviewers with input and guidance
`from OLDP (Dr. Rammh Raghavachari BC, OLDP). The applicant was advised to
`amend the comparability protocol to include stability data on three batches in each
`packaging configuration. The applicant agreed and the comparability protocol was
`deemed acceptable by the review team.
`
`Biopharmaceutics
`The acceptability ofthe proposed dissohrtion method and acceptance criterion for the
`muflneQCtesfingoftheproposeddmgprodmtatbatchmleasemdonsmbflitywas
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 4 of 7
`
`Bflecfive Date: 14 February 2017
`
`

`

`"'"""‘
`Islam}
`
`QUALITY ASSESSMENT
`
`""“‘"‘
`mm:
`
`assessed. The dissohltion method included a USP Apparatus II (Paddle) at 50 rpm in
`900mLof0.lNHCl. Theproposeddissolution acceptance criterionis
`%in20
`minute. ItisnotedfliatthedrugsubstanceisaBCS classZeompoundandis 'ghly
`soluble in acidic media up to pH 4. Both the proposed dissolution method and
`acceptance cn'terion were deemed acceptable and as such this application is
`recommended for approval from a biopharmaceutics perspective.
`
`PBPK Model
`
`The applicant proposed a Physiologically Based Pharmacokinetic (PBPK) model to
`support aparticle size specification ongoNMT- um forthe drug substance. The
`information provided was incomplete and therefore does support the approval of the
`PBPK model. While the proposed PBPK model is not acceptable, this
`recommendation has no impact on the
`vability of the NDA submission, because
`the newly proposed limit ofD90: NMT
`pm for the particle size of the drug
`substanceisbasedontheactuangopartlc esizelimitofthe drugproductusedinthe
`pivotal clinical batches, which is acceptable.
`
`Facilities
`
`
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 5 of 7
`
`Bflecfive Date: 14 February 2017
`
`

`

`
`
`USE of CLINICAL BATCH for COMMERCIAL LAUNCH:
`
`The sponsor submitted a proposal to ensure that acalabrutinib capsules would be
`available to meet a potential October 2017 approval. Specifically, the sponsor
`presented a supply option to meet this accelerated timeframe which included using
`material from the product validation campaign. During a Type A meeting
`teleconference held on August 17, 2017, the applicant requested the FDA’s approval of
`API clinical batch C665/2 manufactured at AstraZeneca of the UK (FEl 3002850317) for
`use in one batch of commercial Acalabrutinib capsules in order to ensure availability of
`market launch supply upon approval of this application. To facilitate a risk assessment
`of the quality of batch C665/2 additional coverage was given to the manufacturing
`systems and records related to the C665 campaign manufactured at AstraZeneca.
`Review of the records for the production and testing operations, cleaning and
`qualification of facilities & equipment, and the resolution of deviations and
`investigations associated with the manufacture of the drug product batch C665/2
`revealed no adverse findings that would pose a risk to use of the batch in drug product
`intended for commercial supply. Accordingly, the use of drug substance batch C665/2
`for a commercial batch of capsules is acceptable. The corresponding commercial drug
`product batch number is L06051].
`
`Environmental Assessment
`
`The applicant provided a claim for categorical exclusion and a statement of no
`extraordinary circumstances under 21 Code of Federal Regulations (CFR) Sections
`25 .3 l (b).
`
`The request for categorical exclusion is granted.
`
`OPQ-XOPQ-TEM—0001v04
`
`Page 6 of 7
`
`Effective Date: 14 February 2017
`
`

`

`
`
`C. Special Product Quality Labeling Recommendations (NDA only)
`nla
`
`D. Final Risk Assessment (see Attachment)
`Appended at the end of the drug product review.
`
`OPQ-XOPQ-TEM—0001v04
`
`Page 7 of 7
`
`Effective Date: 14 February 2017
`
`

`

`Sherita
`McLamore
`
`Digitally signed by Sherita McLamore
`Date: 10/17/2017 09:18:09AM
`GUID: 503257950000415755492db5bb8b1a5c
`
`74 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`mmmrmmm
`
`QUALITY ASSESSMENT
`
`kmmh‘ntmum
`
`LABELING 1E le 210259!
`
`R
`
`Regional Information
`
`1.14 Labeling
`
`Labeling & Package Insefl
`
`DESCRIPTION section:
`
`ll_!_PE§§ZBJ_1?._T_T_9N_____________________________________________________________________________________________________________
`
`TRADENAMB (“alabrufinm is mighihiw.91: §IQE991¥9§PQKWQEC§IK12IH€ 21919991.?! @319?.....
`for acalabrutinib is Old-123N701, and the molecular weight is 465 .5 1. The chemical name is 4-{8-amino-
`
`‘
`
`3 -[(2 S)- l -(but-2-ynoyl)pyrrolidin-2-yl]imidazo[ l ,5 -a]pyrazin- l -yl)} -N—(pyridine-2-yl)benmmide.
`
`The chemical structure ofacalabrutinib is shown below:
`
`NH,
`
`N
`
`(S)
`
`NaK
`
`mmpowder with pH-dependent solubility. It is freely soluble in water at pH
`Acalabrutimb is a white to
`values below 3 and practically insoluble at pH values above 6.
`
`TRADENAME capsules for oral administration contains 100 mg acalabrutinib and the following inactive
`ingredients: microcrystalline cellulose,
`a.)(”partially pregelatinized starch,
`magnesium stearate, and sodium starch glycolate. The capsule shell contains gelatin, titanium dioxide,
`
`yellow iron oxide, FD&C Blue 2 and is imprinted with edible black ink.
`
`Is the information accurate? g Yes
`If ”No,” explain.
`
`I: No
`
`Is the drug product subject of a USP monograph? E] Yes X No
`
`Page 1 of 5
`
`

`

`QUALITY ASSESSMENT
`
`If ”Yes,” state if labeling needs a special USP statement in the Description. (e.g., USP test
`
`pending. Meets USP assay test 2. Meets USP organic impurities test 3.)
`
`Note: If there is a potential that USP statement needs to be added or modified in the
`
`Description, alert the labeling reviewer.
`
`HOW SUPPLIED section:
`
`
`‘ 111.6.flgll'fifllifilflpiflgfifigi‘lANDHANDLING.............................................................
`
`How Supplied
`
`Pack Size
`
`Contents
`
`NDC Number
`
`(b)(4)
`
`Bottle containing 60 capsules
`
`blue cap, marked in black ink with ‘ACA 100 mg’
`
`60-count bottle
`
`100 mg, hard gelatin capsules with yellow body and
`
`Storage
`
`Store at [IV-1.2.???“ K§§_€:Z??§);_¢§9!§i99§nemm;9§ F9. 11.5fb3.9‘?9(_5_9_f’_ _-_ §§_°_F_). 1.52:95299999119‘2. __________
`Room Temperature].
`
`i)
`
`Is the information accurate? X Yes D No
`
`If "No,” explain.
`
`ii)
`
`Are the storage conditions acceptable? E Yes
`
`[:I No
`
`If ”No,” explain.
`
`DOSAGE AND ADMINISTRATION sectionI tor infectablesI and where applicable:
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Reconmnended [Dosage]_________________________________________________________________________________________________
`
`The recommended dose of TRADENAME is 100 mg taken orallv a
`
`
`until disease progression or unacceptable toxicity.
`
`éQECiFPPEEiSFIS. 395331.193: @919 .With. .‘YI‘HSE-ég‘fii? ratifies. .1591I9..92?9-_¥2¥?a1.<_9!.99?§3'.Ih¢.9§9§91€§- ......
`TRADENAME may be taken with or without food-if, ,a, 995?, 9fTRADENAME is, missedhqu than, 3,,
`hours, it should be skipped and the next dose should be taken at its regularly scheduled time. Extra
`capsules of'I'RADENAME should not be taken to make up for a missed dose.
`
`roximatelv eveiv twelve hours
`
`
`Page 2 of 5
`
`

`

`
`
`
`
`
`
`Immediate Container Label (100mg:_ 60 countsz
`
`Page 3 of 5
`
`

`

`QUALITY ASSESSMENT
`
`Reviewer’s Assessment:
`
`The following comments were communicated to the applicant on 14-SEP-2017 by DMEP. The
`applicant has not responsed to deficiencies yet. Responses pending
`
`1 2 Replace the temt "TRADENAM " with the conditionally acceptable
`
`proprietafl name.
`
`22 Relocate the net guantiQ statement (60 capsules) away tom the product
`
`strength (100 mg), such as to the bottom at the principal displfl panel. From
`
`post-marketing experience, the risk at numerical confiion between the
`
`strength and net guantig increases when the net quantiQ statement is located
`
`in close proximity to the strength statement. Drafl Guidance: Container and
`
`Cartonl April 2013 (Zines 461-4632.
`
`32 As currently presented, there is no space allotted tor the lot number and
`
`expiration. The lot number statement is regpired on the container and carton
`
`labelin when there is su cient s ace er 21 CFR 201.10 i 1 . Please ensure the
`
`lot number is clearly diflerentiated tom the expiration date. In additionI please
`
`ensure that there are no other numbers located in close proximigz to the
`
`expiration date where it can be mistaken as the expiration date.
`
`42 Update the NDC numbers in the PI and Container Closure labels.
`
`A separate memo will befiled in Panorama, once the Agency received an agreed upon labeling
`and labels. Pending
`
`Conclusion: Labels and Labeling are not adequatefrom a CMC standpoint.
`
`Primary Labeling Reviewer Name and Date:
`
`Rajiv Agarwal, PhD, l4-SEP-2017
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`Anamitro Banerjee, PhD, Acting BC, September 15, 201 7
`
`Page 5 of 5
`
`

`

`Rajiv
`Agarwal
`
`Anamitro
`Banerjee
`
`Digitally signed by Rajiv Agarwal
`Date: 9/19/2017 11:32:39AM
`GUID: 504fa29c0000100b83d3aaa4905783c1
`
`Digitally signed by Anamitro Banerjee
`Date: 9/19/2017 01:55:57PM
`GUID: 5075764700003844b7bc89632228509f
`
`34 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following
`this page
`
`

`

`2
`
`BIOPHARMACEUTICS
`
`NDA: 210259-ORIG-1
`
`Drug Product Name/Strength: Acalabrutinib Capsules, 100 mg
`
`Route of Administration: Oral
`
`Applicant Name: Acerta Pharma B.V.
`
`Product Background:
`
`Acalabrutinib is a kinase inhibitor indicated for the treatment of patients with Mantle Cell
`Lymphoma (MCL) who have received at least one prior therapy. The recommended dose is 100
`mg orally twice daily taken with or without food.
`
` hard gelatin capsule, with a blue cap and
`The proposed drug product is presented as a
`yellow body, printed with ‘ACA 100 mg’ in black ink and containing 100 mg of acalabrutinib.
`
`REVIEW SUMMARY:
`
`Submission: Acerta Pharma B.V. submitted this NDA seeking approval for Acalabrutinib
`Capsules 100 mg under section 505 (b)(1) of the Federal Food, Drug, and Cosmetic Act.
`
`Reviewer’s Assessment: The Biopharmaceutics Review evaluates the adequacy of the proposed
`dissolution method and acceptance criterion for the routine QC testing of the proposed drug
`product at batch release and on stability.
`
`The following dissolution method and acceptance criterion for the proposed Acalabrutinib
`Capsules 100 mg are acceptable:
`Apparatus:
`Speed:
`Medium:
`Volume:
`Temperature:
`Dissolution acceptance criterion:
`
`USP Apparatus II (Paddle)
`50 rpm
`0.1 N HCl
`900 mL
`37 °C
`Q = % in 20 minutes.
`
`Recommendation: From the Biopharmaceutics perspective, NDA-210259 for Acalabrutinib
`Capsules, 100 mg, is recommended for APPROVAL.
`
`List of submissions being reviewed: Original NDA-210259 submitted on June 13, 2017.
`
`Highlight of key outstanding issues from last cycle: None.
`
`Concise description of outstanding issues: None.
`
`2
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`3
`
`REVIEW:
`
`1. BCS Designation:
`
`The Applicant reported that acalabrutinib is a BCS class 2 compound (low solubility and high
`permeability). The Applicant reported that the drug substance is highly soluble in acidic media
`up to pH 4.
`
`Table 1. Solubility of acalabrutinib in different pH media at 37 °C (Page 44, Module 2.7.1)
`
`The Applicant also measured the equilibrium solubility of acalabrutinib in Fasted State
`Simulated Intestinal Fluid (FaSSIF, pH=6.5, 0.12 mg/mL), and in Fed State Simulated Intestinal
`Fluid (FeSSIF, pH=5.0, 0.67 mg/mL).
`
`2. Dissolution method:
`
`The proposed dissolution method for Acalabrutinib capsules 100 mg is as follows:
`Apparatus:
`USP apparatus II (Paddle)
`Paddle Speed:
`50 rpm
`Medium:
`0.1 N HCl
`Volume:
`900 mL
`Temperature:
`37 ºC
`
`3
`
`(b) (4)
`
`5 Page(s) has been Withheld in Full as b5 immediately following this page
`
`

`

`9
`
`4. Dissolution data and proposed dissolution acceptance criterion for the Acalabrutinib
`capsules, 100 mg:
`
`The Applicant provided the dissolution profile data for different batches used in clinical studies
`(refer to Table 3 for more batch information) using the proposed dissolution method (Figure 10).
`
`Figure 10. Dissolution profiles of the proposed Acalabrutinib capsules, 100 mg, using the proposed
`dissolution method
`
`9
`
`(b) (4)
`
`

`

`10
`
`Reviewer’s Assessment of the Proposed Dissolution Acceptance Criterion: Based on the
`dissolution data, the Applicant’s proposed dissolution acceptance criterion of Q =
` % dissolved
`in 20 minutes for Acalabrutinib capsules 100 mg is acceptable.
`
`5. Stability data:
`
`The Applicant provided stability data for Batches L0505009, L0505541, L0506080 L0508305,
`L0508623, and L0508625 packaged in bulk pack, or in 60 mL HDPE bottle, or in 110 mL HDPE
`bottle under 25°C/60% RH up to 18 months, 30°C/75% RH up to 18 months, and 40°C/75% RH
`up to 6 months. The stability dissolution data indicate that these batches meet the dissolution
`acceptance criterion of Q = % in 20 minutes in different storage conditions.
`
`Reviewer’s Assessment: The Applicant provided the stability dissolution data at 12 months using
`the proposed dissolution method and all samples passed the dissolution acceptance criterion at
`Stage 1. Therefore, the proposed drug product is stable with regards to dissolution for at least 12
`months under long term storage conditions.
`
`6. Bridging between the
`
`capsules and planned commercial products:
`
`capsule formulations were used in some pivotal clinical studies and supportive
`The
`studies (Table 3). The
`capsule formulations contain
`
`
`
`
`
`
`
` Figure 11 below demonstrates that the
`
`.
`
`In addition, the Applicant reported that the pharmacokinetic (PK) exposure was generally similar
`between 100 mg acalabrutinib in either
` capsule or the intended commercial formulation
`in healthy subjects and on Cycle 1 Day 1 in patients.
`
`10
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`11
`
`Table 3. Difl'erent Acalabrutinil) formulations used in clinical studies. The “Capsule” in the column
`
`labeled “Brief Description” is the intended commercial formulation
`Drug Product
`Study
`Brief
`Strength (mg) Manufacturing
`Bulk Lot
`Description‘
`Facility
`
`ACE-HV-00 l
`NCZP
`
`
`NCZS
`ACE-HV-OOI
`
`
`
`1.0505009
`ACE-HV-OOS
`capsule
`
`apsule
`15
`STGY
`ACE-HV-007
`
`
`NVTF
`
`ACE-HV-004
`
`
`
`apsule
`
`25
`
`ACE-HV-008
`
`NCZS
`L0505009
`
`
`
`1.0 mg/mL
`
`
`(~ 1 0 nCi/mL)
`
`
`
`l .64 pg/mL
`["C]acalabrutinib
`
`
`ACE-HV-009
`(~200 nCi/mL)
`IV solution
`
`
`STGY
`ACE-HV- l l 1
`
`L0505009
`ACE-HV- l l 2
`capsule
`100
`
`W026394
`ACE-HV-l l 3
`capsule
`100
`
`
`
`NZCP
`ACE-HI-OOI
`
`
`
`
`
`
`capsule
`100
`
`
`
`
`
`
`
`L05075 52
`ACE-CL-OOI
`capsule
`100
`
`
` L0508306 ACE-CL—OO]
`
`NVTF
`ACE-LY-002
`
`ACE-HV—009
`
`capsule
`
`l 00
`
`ACE-HV-009
`
`["C]acalabrutinib
`oral solution
`
`capsule
`
`l 5
`
`NFYY
`
`NVTF
`
`PMFS
`
`SHGZ
`
`SVZB
`
`W025985
`
`W026394
`
`W027 180
`
`W032242
`
`L0505009
`
`L050554 1
`
`L0506080
`
`ACE-CL-OOI
`
`ACE-CL-OOI
`
`ACE-CL-OO]
`
`ACE-CL-OOI
`
`ACE-CL-OO]
`
`ACE-CL-OOI
`
`ACE-CL-OOI
`
`capsule
`
`ACE-CL-OOI
`
`ACE-CL—OOI
`
`ACE-CL-OO]
`
`ACE-CL—OO]
`
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`

`13
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`(mo capsule batches and the proposed commercial batches
`Figure 11. Dissolution profiles of
`Butch Number
`(5) (”capsule
`Conunerc-al
`6040! by
`.NW:
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`
`7. Bridging between the capsules manufactured at different sites:
`
`(mo and the
`Acalabrutinib Capsules manufactured at the development site
`commercial manufacturing facility
`(mo were used in clinical studies
`
`(Table 3). The Applicant reported that the clinical formulations and the intended commercial
`products are
`(low
`
`More than 85% was dissolved for all formulations using the proposed dissolution method (Figure
`
`12). Therefore, similar comparative dissolution profiles were demonstrated for the proposed drug
`
`product batches manufactured at different sites.
`
`Figure 12. Comparative dissolution profiles for different Acalabrutinib Capsule formulations used
`
`in clinical studies using the proposed dissolution methodCoot ay
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`
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`
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`
`13
`
`

`

`REVIEWER’S OVERALL ASSESSMENT:
`
`14
`
`Dissolution Method: The proposed dissolution method [USP apparatus II (Paddle)/50 rpm/900
`mL of 0.1 N HCl] is acceptable for the quality control of the proposed immediate release drug
`product, Acalabrutinib capsules, 100 mg, as part of the batch release and stability testing.
`
`Dissolution Acceptance Criterion: The proposed dissolution acceptance criterion of NLT %
`(Q) of the labeled amount of acalabrutinib dissolved in 20 minutes for the proposed
`Acalabrutinib Capsules 100 mg is acceptable.
`
`RECOMMENDATION:
`
`From the Biopharmaceutics perspective, NDA 210259 for Acalabrutinib Capsules, 100 mg, is
`recommended for APPROVAL.
`
`Primary Biopharmaceutics Reviewer:
`Yang Zhao, Ph.D.
`Division of Biopharmaceutics
`Office of New Drug Products/OPQ
`
`9/28/2017
`
`Secondary Biopharmaceutics Reviewer:
`I concur with Dr. Yang Zhao’s assessment and APPROVAL recommendation.
`
`Okpo Eradiri, Ph.D.
`Acting Biopharmaceutics Lead
`Division of Biopharmaceutics
`Office of New Drug Products/OPQ
`
`10/2/2017
`
`14
`
`(b) (4)
`
`

`

`Yang
`Zhao
`
`Digitally signed by Yang Zhao
`Date: 10/04/2017 09:28:36AM
`GUID: 56f958740001a1f9707b4476d760e12f
`
`Okponanabofa
`Eradiri
`
`Digitally signed by Okponanabofa Eradiri
`Date: 10/04/2017 01:18:16PM
`GUID: 50bdfe8d00003559ede66be3fd299f65
`
`

`

`QUALITY ASSESSMENT Chapter VII - BIOPHARMACEUTICS
`
`kalmranlmwc-mfim-
`
`drawn-almanac»
`
`ADDENDUM TO ORIGINAL BIOPHARMACEUTICS REVIEW
`
`
`
`Application No.: NDA 210259; 505(b)(l)
`
`Applicant/Sponsor:
`Acelta Pharma B.V.
`
`
`Product Name:
`Acalabrutinib Capsules, 100 mg
`
`Primary Reviewer:
`Yang Zhao, Ph.D.
`
`Secondary Reviewer:
`
`Fang Wu, Ph.D.
`
`Tertiary Reviewer:
`
`Okpo Eradiri, PhD.
`
`
`
`Biopharmaceutics Branch Chief: Angelica Dorantes, Ph.D., Kimberly Raines, Ph.D.
`
`NOT ACCEPTABLE
`
`Biopharmaceutics Evaluation of the Physiologically Based Pharmacokinetic Model
`Supporting Proposed Particle Size Limit for Acalabrutinib Drug Substance.
`
`REVIEW SUMMARY:
`
`Background: This Addendum to the Original Biopharmaceutics Review Chapter, provides the
`specific details on the Biopharmaceutics evaluation of the proposed Physiologically Based
`Pharmacokinetic (PBPK) model for the proposed particle size limit for Acalabrutinib drug
`substance.
`
`Submission: This NDA submission provided a PBPK model, which was developed with the
`objective of supporting the setting of the particle size limit (D90: NMT (hm um) of the drug
`substance used in the manufacture of the proposed Acalabrutinib Capsules, 100 mg.
`
`Review: The focus of this Biopharmaceutics review was to evaluate the PBPK model and
`provide a recommendation on the model’s acceptability to be used to support the proposed
`particle size limit of D90: NMT (um pm for acalabrutinib drug substance.
`
`Conclusion and Recommendation: The provided information/data was incomplete and
`therefore, did not fully support the approval of the PBPK model. Although the proposed PBPK
`model was not acceptable, it is noted that this recommendation does not have an impact on the
`approvability of the NDA submission, because the newly proposed limit of D90: NMT M" pm
`for the particle size of the drug substance is based on the actual D90 particle size limit of the drug
`product used in the pivotal clinical batches, which is acceptable.
`
`Primary Biopharmaceutics Reviewer:
`Yang Zhao, PhD
`
`Secondary and Tertiary Biopharmaceutics Reviewers:
`Fang Wu, PhD
`Okpo Eradili, PhD
`
`10/6/2017
`
`10/7/2017
`10/10/2017
`
`

`

`QUALITY ASSESSMENT Chapter VII - BIOPHARMACEUTICS
`
`
`:tmmtxnlmmmhuo-
`ummmnumuuno
`
`
`PROPOSED PBPK MODEL:
`
`Purpose of the Model: to support a proposed acalabrutinib drug substance particle size
`specification of D90 of NM'I (m4) pm.
`
`List of submissions being reviewed related to the PBPK model:
`
`Submitted Description
`Date
`
`Reviewed data
`
`6/13/2017
`
`Original submission
`
`3.2.P.2 Pharmaceutical Development
`-P.2 Pharmaceutical Development-Attachment 2: In Silico
`
`Models Development
`1.11.1 Quality Information Amendment-Response to
`Response to Information Request
`7/31/2017
`
`Questions-Quality-July 2017
`Response to Information Request PBPK model data included in
`3.2.P.2 Pharmaceutical Development
`1.11.1 Quality Information Amendment-Response to
`I estions— 0.1i -S .tember 2017
`
`
`
`8/2/2017
`
`9/13/2017
`
`Response to Information Request
`
`3.2.P.2 Pharmaceutical Develo ment
`
`1.2 Cover Letters— Response to FDA CMC Information
`R uest dated October 3, 2017
`
`1.
`
`
`Introduction:
`
`one hard gelatin capsule, with a blue
`The proposed Acalabrutinib Capsules is presented as a
`cap and yellow body, printed with ‘ACA 100 mg’ in black ink and containing 100 mg of
`acalabrutinib (Table 1).
`
`Table 1: Composition of Acalabrutinib Capsules 100 mg
`
`Components
`
`Acalabmtinib
`
`Quantity
`(mg/capsule)
`
`Functlon
`
`Standard
`
`[00
`
`Drug substance
`
`Iii—house specification
`
`Silicified niicrocrystalline cellulose
`
`(”(4)
`
`NF
`
`Partially pregelatinised starch
`
`Sodium starch glycolate
`
`Llagnesium steaiate
`(”(0
`
`USP
`
`NF
`
`USP/NF
`
`Hard gelatin capsule shell“b
`Imprinting ink"
`316
`Total filled capsule weight
`a
`(b) (4)
`yellow and blue. opaque hard gelatin capsule.
`I)
`See Table 2 for full composition of gelatin capsules and imprinting ink.
`This value represents an approximate average capsule shell weight.
`
`c
`
`

`

`QUALITY ASSESSMENT Chapter VII - BIOPHARMACEUTICS
`
`Jmmhnlmmlwx-
`
`umumnmmuum
`
`2. Pharmacokinetic Data:
`
`Observed individual plasma pharmacokinetic profiles from studies ACE-HV-009, ACE-HV-004,
`
`and ACE-HV—l 12 were used in the PBPK modelling.
`
`(healthy
`1
`Study ACE-HV-009 is an absolute bioavailability study conducted for cohort
`volunteers) receiving an oral dose of 100 mg acalabrutinib capsule (Batch No.2 L0505009) and a
`micro-dose of 7.9 mg acalabrutinib solution infused intravenously over 2 minutes at t=58 min
`following oral dosing. Study ACE-HV-004 is a phase 1, 2-period, 3-part study to evaluate the
`interaction of calcium carbonate, omeprazole, or Iifampin on acalabrutinib in healthy adult
`subjects. Study ACE—HV-112 is a phase 1, 4-period, 3-pa11 study in healthy adult subjects to
`evaluate the effect of an acidic formulation of acalabrutinib [acidic formulation of acalabrutinib
`is to increase the acidic microenvironment for the acalabrutinib capsule by adding L-tartaric acid
`and alginic acid (acid diluents)], acidic beverage, or grapefruit juice on the pharmacokinetics of
`acalabrutinib alone and co-administered with omeprazole.
`
`The proposed PBPK model was analyzed using GastroPlus v9.0 (CA) software package. The
`objective of the GastroPlus model was to justify an acceptable limit for drug substance particle
`size.
`
`; Solubilig and Permeabilit_v_ Data:
`
`The Applicant reported that acalabmtinib could be classified as a BCS class 2 compound (high
`permeability and low solubility). Acalabrutinib exhibits pH-dependent solubility across the
`physiological pH range. In acidic conditions up to pH 4, acalabrutinib demonstrates high
`solubility (Table 2), and therefore, the Applicant stated that 100 mg acalabrutinib solid oral
`dosage forms behave as a non-precipitating solution, with low biophannaceutical risk similar to
`highly soluble, highly permeable BCS class 1 compounds.
`
`The Applicant also measured the equilibrium solubility of acalabrutinib in Fasted State
`Simulated Intestinal Fluid GJaSSIF, pH=6.5, 0.12 mg/mL), and in Fed State Simulated Intestinal
`Fluid (FeSSIF, pH=5.0, 0.67 mg/mL).
`
`Table 2: Solubility of acalabrutinib in different pH media at 37 °C
`
`[111
`
`Solubility mg/mL
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`>1 00
`
`>1 00
`
`>1 00
`
`3 .9
`
`0.34
`
`0.077
`
`0.05 l
`
`0.048
`
`I'SP solubility
`description
`
`Freely soluble
`
`Freely soluble
`
`Freely soluble
`
`Slightly soluble
`
`Vety slightly soluble
`
`Practically insoluble
`
`Practically insoluble
`
`Practically insoluble
`
`3
`
`BCS solubility
`description
`
`Dose of acalabrutinib
`soluble in 250 mL (mg)
`
`High
`
`High
`
`High
`
`High
`
`Low
`
`Low
`
`Low
`
`Low
`
`>2 5000
`
`>2 5000
`
`>2 5000
`
`97 5.
`
`85
`
`19.3
`
`12.8
`
`12
`
`

`

`QUALITY ASSESSMENT Chapter VII - BIOPHARMACEUTICS
`
`
`kflmrxnlmmmim-
`aroma-Mums: u»
`
`The Applicant assessed acalabrutinib permeability using the in vitro MDCK cell assay and
`pharmacokinetic data from human study ACE-HV-004.
`
`The passive permeability (Papp) from MDCK cell line was assessed at 23.4><10‘6 cm/s which
`was scaled to a human jejunal effective permeability (Peff) of 4.61><10‘4 cm/s using the reference
`correlation (Drug Metabolism & Disposition 2010; 38(7): 1147—1158).
`
`Individual phannacokinetic profiles from study ACE-HV-004 were fitted using a multi-fractional
`dose, 2 compartment PK model. In vivo absorption rates were transformed to effective
`permeability values. For n=64 evaluable subjects the average effective permeability value was
`found to be 6.8:t2.6><10‘4 cm/s with min and max values of 1.8><10*1 and IOXIW cm/s,
`respectively, and a median value of 6.7><10‘4 cm/s.
`
`The Applicant stated that the data from MDCK and human phannacokinetic profiles support
`high permeability of acalabrutinib.
`
`4. Dissolution Data:
`
`The proposed dissolution acceptance criterion of “Q = 8% at 20 minutes” is acceptable,
`indicating that dissolution is not rate limiting with respect to in vivo absorption (Figure 1).
`
`Figure 1: Comparative dissolution profiles for different Acalabrutinib Capsules 100 mg
`formulations used in clinical studies using the proposed dissolution method [USP apparatus 11
`(Paddle) at 50 rpm, 900 mL of 0.1 N HCI at 37 °C]
`
`
`
`
`
`110
`
`100
`
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`
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`
`60
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`40
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