CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208026Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`QUALITY REVIEW
`
`Recommendation:
`
`NDA 208026
`
`Review #1
`
`Review Date (see page 5)
`
`m—
`—_
`—_
`
`«—
`
`
`M
`
`0 uali
`
`' Review Team
`
`DISCIPLINE m DIVISION/OFFICE
`Application Technical Lead
`New Drug Products I/ONDP
`Regulatory Business Process
`Regulatory Business Process
`Manager
`Management I/OPRO
`Muthukumar Ramaswamy
`Drug Product
`New Drug Products II/ONDP
`———xm
`
`Anika Lalmansingh
`
`

`

`QUALITY REVIEW NDA 208026
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
`DATE
`REVIEW
`COMPLETED
`
`CONIMENTS
`
`
`
`ITEM
`REFERENCED HOLDER
`
`
`
`
`(mo Currently adequate to support the approved
`NDA 201281 (linagliptin/metformin HCl, by
`
`the same applicant: reference is provided)
`
`by M.Ramaswamy/D. Christodoulou
`Per MAPP “CMC Reviews of Type HI DMFs
`for Packaging Materials” the referenced Type
`III DMFs need not be reviewed for solid
`
`
`
`
`
`
`
`dosage forms.
`
`
`B. Other Documents:
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
`NDA
`
`2 l 748
`
`Glumetza(metformin HCl)
`Authorized reference from a b - licant Salix
`
`
`
`Same a . licant
`
`Same a . licant
`
`2. CONSULTS: not applicable
`
`

`

`QUALITY REVIEW NDA 208026
`
`1.
`
`Recommendation
`
`Executive Summary
`
`The recommendation from the Office of Pharmaceutical Quality (including the Overall
`Manufacturing Inspection Recommendation) is for APPROVAL.
`
`Labeling comments will be finalized during the multi-disciplinary review managed by
`0ND.
`
`A. Recommendation and Conclusion on Approvability
`1. Summary of Complete Response issues: not applicable
`2. Action letter language: not applicable
`
`B. Recommendation on Post-Marketing Commitments, Agreements, and/or
`Risk Management Steps- not applicable
`
`II.
`
`Summary of Quality Assessment
`This is a 505(b)(1) application but not for an New Molecular Entity. The applicant
`has approved NDAs for the active ingredient linagliptin and fill] right of reference
`to the approved NDA for the active ingredient metformin HCl.
`
`A. Drug Substance
`Chemical Name or IUPAC Name/Structure:
`
`Linagliptin is described chemically as 1H-Purine-2,6-dione, 8-[(3R)-3-amino-
`1-piperidinyl]—7-(2-butyn-l—yl)—3,7—dihydro-3-methyl—l-[(4—methyl-2—
`quinazolinyl)methyl]-, the empirical formula is C25H28N802 and the
`molecular weight is 472.54 g/mol. The structural formula is:
`
`cm FQ
`
`Metformin hydrochloride is N,N—dimethylimidodicarbonimidic diamide
`hydrochloride, with a molecular formula of C4H11N5-HC1 and a molecular
`weight of 165.63. The structural formula is:
`NH
`NH
`Hacx /lL )L
`N
`N
`|
`H
`CH,
`
`NH2
`
`-
`
`HCl
`
`NDA 201280 Tradjenta (linagliptin), by the same applicant, is referenced for
`all CMC information on the drug substance linagliptin. The NDA is currently
`approved and the reference is adequate.
`
`

`

`QUALITY REVIEW NDA 208026
`
`NDA 201281 Jentaduo ((linagliptin/metformin HCl), by the same applicant, is
`referenced for all CMC information on the drug substance metformin HCl.
`The NDA is currently approved and the reference is adequate.
`
`B. Drug Product
`
`The product is a film-coated tablet consist of immediate release saxagliptin and
`extended release metformin HCl, with two strengths: 5 mg/1000 mg and 2.5
`mg/1000
`lina ' tin immediate release Imetformin h drochloride extended
`
` . Pol eth ene oxide is
`
`2.5 mg/1000 mg - yellow oval tablet printed on one side in black ink with the
`BI logo and “D2” on the top line and “1000M” on the bottom line.
`5mg/1000 mg - white oval tablet printed on one side in black ink with the BI
`logo and “D5” on the top line and “1000M” on the bottom line.
`
`Excipients are
`Tablet core
`
`1 ethylene oxide, hypromellose, and magnesium stearate
`
`[Coatings] hydroxypropyl cellulose, hypromellose, talc, titanium dioxide,
`arginine, polyefliylene glycol, ferric oxide yellow (2.5 mg/1000 mg), camauba
`wax, ferrosofern'c oxide, propylene glycol, and isopropyl alcohol.
`
`
`
`The regulatory drug product specification is adequate based on the supporting
`release and stability data and ICH 'delines for this
`of dosage form. It
`
`includes content for Arginine,H
`
`Container Closure: HDPE bottles with desiccant—
`
`Expiration Date & Storage Conditions: 24 months at room temperature
`
`C. Summary of Drug Product Intended Use
`
`not finalizedb GRMP goal; see CDTL’s NonProrie
`
`linaglitufinandmetformin drochlorideextended
`
`NameoftheD_P1-odnct
`
`

`

`not . ulicable
`
`Non Pro orieta Name of the Dru_ Substance
`Pro sed Indication s
`Duration of Treatment
`
`Maximum Dail Dose
`Alternative Methods of Administration
`
`not finalized b GRMP _oal; see CDTL’s memo
`
`QUALITY REVIEW NDA 208026
`
`release tablet
`
`lina_ ' tin and metformin h drochlon'de
`not finalized b GRMP _oal; see CDTL’
`
`D. Biopharmaceutics Considerations
`Three pivotal bioquivalence studies were conducted to compare the three dosage
`strengths to the co-administered single-entity products (details of these studies are
`found in the Clinical Pharmacology review). With the exception of printing ink
`, the formulation is the same for the clinical batches, stability
`batches, and commercial product.
`1. BCS Classification
`
`0 DrugSubstance: BomoflimgliptinanndlfinminHClarc
`considered as BCS III compounds (high solubility, low
`permeability)
`0 Drug Prochct: BCS 111
`
`Note: bl Module 2.31’ and Module 3. 21’. 2, the Applicmt
`indicated that “Linaglipfin 8 considered a Class at compound
`(high solubility, lowpermeability) according to the
`Biophannaceutical Classification systan (BCS)”, "Mefwmin
`HCI is also considered a Class at compound fltigh solubility,
`lowpermeability) according to the Biophamaceutical
`Classg‘ication systan (BCS)
`
`2. Biowaivus/Biosuulies
`
`o Biowaiver Requests: No Biowaivcr request
`0 PKsmdies:0neBAstudy(smdy#1288.8)andMoBEsmdies
`(study# 1288.9 for 5mg/1000mg and study# 138.11 for
`2.5mg/1000mg) were submitted and reviewed by the Office of
`Clinical Pharmacology (OCP)
`IVIVC: No IVIVC
`
`0
`
`E. Novel Approaches: not applicable
`F. Any Special Product Quality Labeling Recommendations: not applicable
`G. Life Cycle Knowledge Information (see Attachment)
`
`OVERALL ASSESSMENT AND SIGNATURE:
`
`EXECUTIVE SUNIMARY
`
`
`
`

`

`
`
`1.
`
`Review of Common Technical Document-Quality (Ctd-Q) Module 1
`
`Labeling & Package Insert
`
`1. Package Insert
`
`Reference ID: 39421 63
`
`

`

`QUALITY ASSESSMENT
`
`(a) “Highlights” Section (21CFR 201.57(a))
`JENTADUETO® XR (Linagliptin and metformin hydrochloride extended-
`release) tablets
`
`Controlled drug substance symbol
`if - ulicable
`
`
`
`
`
`Information
`Provided in NDA
`
`Reviewer’s Assessment
`
`-
`
`
`Eroduct title, Drug113316015th 2
`Jentadueto XR
`Proprietary name and established
`
`name
`
`Linagliptin and
`
`
`metformin
`
`
`h drochloride
`
`
` 'Bsgage‘f‘amrm“_‘
`Extended release
`
`
`administration
`tablet, Oral
`
`Not applicable
`
`
`
`2.5mg Linagliptin/ 1000 mg
`A concise summary of dosage forms 25mg Linagliptin/
`
`
`
`Metformin HCl extended release
`and strengths
`Metfonnin HCl
`
`
`
`extended release
`
` 5mg Linagliptin/ 1000 mg
`
`
`Metfomiin HC] extended release
`5mg Linagliptin/
`
`
`Metformin HCl
`
`
`extended release
`
`
`
`Conclusion.
`
`A l99‘) Food and Drug Administration Draft Guidance for Industry states: "A dosage form is the
`
`way of identifying the drug, in its. physical fonn.
`
`In detennining dosage form. FDA examines
`
`such factors as (l _) physical appearance ofthe drug product. (2) physical form of the drug, product
`
`prior to dispensing to the patient. (3') the way the product is administered. (4) frequency of
`dosing. and (5) how pharmacists and other health professionals might recognize and handle the
`
`product."
`
`dgsjitgjregnclig as compared to that drug presented in. conventional dosage form
`
`Among the several possible dosage form designation for the product. CMC Reviewer
`
`recommends Tablet. Extended Release as the most. suitable designation for the dosage form. The
`
`proposed dosage form is to reduce the dosing frequency. It is also film coated. One ofthe coating
`
`layer contains Linagliptin for immediate release This recommendation is consistent with the
`
`definition provided under USP < l 15D Pharmaceutical dosage forms for Extended-release
`
`tablets. Extended-release tablets are formulated in such a manner as to make the drug substance
`
`in ailable over an extended period of time following ingestion.
`
`Reference ID: 39421 63
`
`

`

`
`
`laliletFil_nl t _oateg‘Exit;n_ded Relgase- «solid dosag: form that contains medicinal Substanas with or
`without suitable diluents and Is coated with a thin layer ofn water-Insoluble 01‘ water-soluble polymer, the
`
`tablet Is formulated in such mannei as to make the contained medicament available over an extended period
` oi‘timc followtng Ingestion.
`lablgt n_1_ulti--|_a3;eI _e_x_1_e_r_1_d_ed_L;lags_e_(Tab_l§Ih_‘ll_)le_-1¢LV_€£BJ
`- A solid dosage form containing medicinal
`
`substances that have been compressed to town a InulIIpte-layercd tablet or a tablet-within-a-Iablet. theInner
`
`QUALITY ASSESSMENT
`
`
`
`
`
`
`tablet being the core and the outer portion being the shell. which. additionally. Is covered In a deSIgnated
`
`
`coating, the tablet is fonnulat'ed in such manneI as to allow at least a reduction in dosing frequency as
`
`
`compared to that drug presented as a conventional desage form.
`
`(b) “Full Prescribing Information” Section
`
`# 3: Dosage Forms and Strengths [21CFR 201-57lcl14ll
`
`JENTADUETO XR is a combination of Linagliptin and extended-release metformin
`hydrochloride. JENTADUETO XR tablets are available in the following dosage forms and
`strengths:
`0
`S mg/1000 mg are white, oval-shaped coated tablets with one side printed in black ink with
`the Boehringer lngelheim logo and “D5” on the top line and “1000M” on the bottom line.
`2.5 mg / 1000 mg are yellow, oval-shaped coated tablets with one side printed in black ink
`with the Boehringer lngelheim logo and “D2” on the top line and “1000M” on the bottom
`line.
`
`0
`
`
`
`
`_ Information Providedm NDA
`Available dosa-e forms _
`
`
`
`2.5mglinagliptin11000mg _metformin HCl extended release
`
`
`
`
`
`adequate
`
`Strengths: in metricsystem
`
`
`
`
`
`
`
`
`
`
`
`A description of the identifying 5 mg Linagliptin/ 1000 mg
`characteristics of the dosage
`metformin hydrochloride extended-
`release tablet — description specified.
`forms, including shape, color,
`coating, scoring, and
`
`
`2.5 mg Linagliptin/ 1000 mg
`imprinting, when applicable.
`
`
`
`metformin hydrochloride extended-
`
`release tablet - descri -tion 5 . cified.
`
`
`Conclusion: Adequate
`
`Reference ID: 39421 63
`
`

`

`QUALITY ASSESSMENT
`
`#11: Description (21CFR 201.57gc)112))
`JENTA DUETO XR consists of an extended-release metformin core tablet that is spray-coated
`with four layers, one of which contains the immediate-release drug substance Linagliptin.
`
`JENTADUETO XR is available for oral administration as tablets containing 5 mg Linagliptin and
`1000 mg metformin hydrochloride extended-release (JENTADUETO XR 5 mg/ 1000 mg) or 2.5
`mg Linagliptin and 1000 mg metformin hydrochloride extended-release (JENTADUETO XR 2.5
`mg/ 1000 mg). Each coated tablet of JENTADUETO XR contains the following inactive
`ingredients: Tablet core: polyethylene oxide, hypromellose, and magnesium stearate. Coatings:
`hydroxypropyl cellulose, hypromellose, talc, titanium dioxide, arginine, polyethylene glycol,
`ferric oxide yellow (2.5 mg /1000 mg), camauba wax, ferrosoferric oxide, propylene glycol, and
`isopropyl alcohol.
`
`2.5 mg Linagliptin /1000mg
`metformin l-lCl
`
`
`
`
`
`
`Established name not
`specified
`.
`
`Adequate
`
`Adequate
`
`Adequate
`
`_ Information Provided in NBA
`Proprietary name and established
`JENTADUETO XR
`name
`Linagliptin and metformin HCl
`extended release
`
`Dosage form and route of
`administration
`
`Tablet, extended release.
`oral
`
`
`
`
`
`
`
`
`Active moiety expression of
`strength with equivalence statement
`
`
`for salt (if applicable)
`5mg Linagliptin /1000mg
`
`metformin HCl
`
`
`
`
`Inactive ingredient information
`Tablet core: polyethylene oxide,
`
`
`(quantitative, if injectables
`hypromellose, and magnesium
`
`21CFR201 .1 00(b)(5)(iii)), listed by
`stearate. Coatings: hydroxypropy]
`
`
`
`U SP/N'F names.
`
`cellulose, hypromel lose, talc,
`titanium dioxide, arginine,
`
`polyethylene glycol, ferric oxide
`
`yellow (2.5 mg /1000 mg),
`
`camauba wax, ferrosoferric oxide,
`
`propylene glycol, and isopropyl
`alcohol.
`
`
`_-—I——
`
`Chemical name, structural formula, Specified——_
`
`a. I licable
`
`If radioactive, statement of
`
`Not applicable
`
`Other important chemical or
`
`Specified
`
`solubili
`
`, or H
`
`
`
`
`
`
`Conclusion: Adequate information available for review.
`
`Reference ID: 39421 63
`
`

`

`QUALITY ASSESSMENT
`
`#16: How Su
`
`lied/Stora e and Handlin
`
`21CFR 201.57 c 17
`
`JENTADUETO XR (Linagliptin and metformin hydrochloride extended-release) tablets
`5 mg/ 1000 mg are supplied as follows:
`Bottles of 30 (NDC 0597-0275-33)
`Bottles of 90 (NDC 0597-0275-81)
`
`JENTADUETO XR (Linagliptin and metformin hydrochloride extended-release) tablets
`2.5 mg/1000 mg are supplied as follows:
`Bottles of 60 (NDC 0597-0270-73)
`Bottles of 180 (NDC 0597-0270-94)
`
`Storage
`Store at 25°C (77°F); excursions permitted to l5°-30°C (SW—86°F) [see USP Controlled Room Temperature]. Protect from
`exposure to high humidity. Store in a safe place out of reach of children.
`
`_ Information Provided in NBA
`
`
`
`
`
`
` e.g., shape, color, coating,
`scoring, imprinting, NDC
`number
`
`Deficiency
`Shape, color, coating, scoring,
`imprinting not specified
`
`
`
`
`
`
`
`
`
`Store at 25°C (77°F); excursions
`Storage conditions
`
`permitted to 15°-30°C (59°-86°F)
`
`[see USP Controlled Room
`
`Temperature].
`
`
`
`Manufacturer/distributor name listed at the end of PI, following Section #17
`
`
`
`_ Information Provided in NBA
`Manufacturer/distributor name (21
`CFR 201.1
`
`
`
`
`
`
`Conclusion: Add the following to section 16 (to be communicated to the applicant during labeling
`discussions):
`
`Size , shape, color, and imprinting information for both strength tablets.
`
`2. Container and Carton Labeling
`
`1)
`
`Immediate Container Label
`
`Reference ID: 39421 63
`
`

`

`
`
`Reviewer's Assessment:
`
`Reference ID: 39421 63
`
`

`

` (“an
`QUALITY ASSESSMENT
`
`Conclusions
`
`
`
`Comment on the
`
`
`Information Provided in
`
`NBA
`
`
`'roprietary name, established name (font size Jentadueto XR— Proprietary
`
`and prominence (21 CFR 201.10(g)(2))
`name
`
`
`
`
`inagliptin and metfonnin
`‘
`
`
`
`HCl extended release tablets
`
`
`.trength (21CFR 201.10(d)(l); 21.CFR
`2.51ng/1000mg and 5 mg/1000 Adequate
`r 01.100(b)(4))
`mg
`
`I' oute of administration 2] .CFR
`Oral
`01 .100(b)(3))
`
`
`
`et mutants" (21 CFR 201.51(a))
`60 and 180 counts -
`
`2.5mg/1000 mg ER tablets
`30 and 90 counts - 5mg/ 1000
`
`mg ER tablets
`ot specified
`
`>>9’>o.a.8'a.o“.9,8.r:-°C:ccg,t:9’.31"t2’.(ao0a
`
`
` I ame of all inactive ingredients (Quantitative
`ingredient information is required for
`
`
`njectables) 21CFR 201 .100(b)(5)**
`I ot number per 21 CFR 201.18
`I xpiration date per 21 CFR 201.17
`i ‘Rx only” statement per 21 CFR
`01 .100(b)(1)
`
`
`Store at 25°C (77°F)
`Storage
`
`excursions permitted to 15° to
`(not required)
`
`30°C (59°-86°F)
`
`Specified
`Specified
`Specified
`
`
`
`
`
`
`I
`l C number
`per 21 CFR 201.2)
`
`
`requested, but not required for all labels or
`
`labeling), also see 21 CFR 207.35(b)(3)
`
`
`Specified
`
`
`
`
`
`
`
`Available
`Provided
`
`
`
`
`
`Bar Code per 2| CFR 201 25(c)(2)***
`1 ame of manufacturer/distributor
`(21 CFR 201.1)
`
`
`l_
`‘21 CFR 20] Sl(h) A drug shall be exempt from compliance With the net quantity declaration required by this section if it is an
`ointment labeled “sample", “physician's sample”, or a substantially similar statement and the contents of the package do not exceed
`8 grams.
`“For solid oral dosage forms, CDER policy provides for exclusion of “oral” from the container label
`“Not required for Physician’s samples. The bar code requirement does not apply to prescription drugs sold by a manufacturer,
`rcpacker, relabeler, or private label distributor directly to patients, but versions ofthe same drug product that are sold to or used in
`hospitals are subject to the bar code requirements.
`
`Evaluation: Adequate
`
`2) Carton Labeling
`Carton label for professional sample (5mg 7ct and 2.5mg l4ct) available. Carton
`Labelsfor commercial presentation are not provided.
`
`Reference ID: 39421 63
`
`

`

`
`
`Reference ID: 39421 63
`
`

`

`
`
`
`Conclusrons
`
`
`
`~ dequate
`information
`
`'
`rovided in the label
`
`
`
`
`pecmed
`Not specified
`
`‘
`
`'
`
`'e2we09.aSin:9%%3ca:9- OB)5-1"m
`
`3»
`"U
`
`vailable
`rovided
`
`Yes
`
`Specified
`
`ot required
`
`
`
`3
`i
`
`
`
`
`
`
`“BEAMS-.454-“
`
`QUALITY ASSESSMENT
`
`Proprietary name, established name (font size and
`prominence (FD&C Act 502(c)(l)(A)(i), FD&C
`Act 502(c)(l)(B), 21 CFR 20 | . l 0(g)(2))
`trength (ZlCFR 201.10(d)(l); 2] .CFR
`I 01. 100((d)(2))
`
`NDA
`
`entadueto XR— Proprietary name
`Linagliptin and metformin HCl extended
`release tablets
`
`2.5mg11000mg and 5 mg/ 1000 mg
`
`14 counts - 245mg/ 1000 mg ER tablets
`' '
`14 counts - 5mg! 1000 mg l-IR tablets
`
`I ame of all inactive ingredients (except for oral
`. rugs); Quantitative ingredient information is
`
`equired for injectables)[ 201.10(a),
`
`v lCFR201.100(d)(2)}
`
`
`
`
`
`s terility Information (if applicable)
`
`"Rx only” statement per 2] CFR 201.100(d)(2),
`-D&C Act 503(b)(4)
`
`~excursismm:wemspermmerno
`I
`IC number
`at specified
`per 2] CFR 201.2)
`‘ requested, but not required for all labels or
`abeling), also see 21 CFR 207.35(b)(3)
`
`
` Bar Code per 21 CFR 201.25(c)(2)**
`
`‘ ame of manufacturer/distributor
`
`"See package insert for dosage information” (21
`FR 201.55)
`‘Kcep out of reach of children” (optional for Rx,
`quired for OTC)
`I' oute of Administration (not required for oral, 21
`FR 201.100(d)(l)and (d)(2))
`
`
`
`Conclusion: Adequate information for the carton label used professional sample is provided
`in the NDA.
`
`Carton label for commercial packaging is not available for review. This information
`
`
`
`
`
`
`will be discussed during labeling discussions.
`
`OVERALL ASSESSMENT AND SIGNATURES: LABELING
`
`Reference ID: 39421 63
`
`

`

`
`
`11. List of Deficiencies To Be Resolved During Libeling Discussion
`
`Label/Labelin Deficiencies:
`
`
`
`
`o be resolved durin labelin discussion
`
`
`a) Product identification (Size, shape, color, and imprinting) information is not specified for
`both strength tablets the package insert under Section16 - How supplied and
`Storage/handling instructions).
`
`Reference ID: 3942163
`
`

`

`
`
`BACKGROUND
`
`The Applicant, Boehringer Ingelheim Pharmaceuticals, Inc, submitted this NDA 208026
`on 07/27/2016 for their proposed drug product, Linaglipin/Metformin HCl Extended-
`Release Fixed Dose Combination (ER-FDC) Tablets, 25 mg/ 1000 mg and 5 mg/ 1000
`mg.
`It is indicated as an adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin
`is appropriate.
`
`This submission is a 505(b)(1) application. The Division of Biopharmaceutics (DB)
`focuses on the reviewing of:
`0
`In vitro dissolution test and acceptance criteria of the proposed drug product;
`0
`In vitro alcohol dose dumping studies of the proposed drug product.
`
`BIOPHARMACEUTICS ASSESSMENT
`
`l. The composition of proposed drug product formulation
`
`The two strengths of the to-be-marketed (TBM) formulation and composition of the
`proposed drug product, Linaglipin/Metformin HCl ER—FDC Tablets, 2.5 mg/ 1000 mg
`and 5 mg/ 1000 mg, are shown in Table 1.
`
`20
`
`OPQ-XOPQ-TEM-0001v02 Effective Date: 13 Mar 2015
`
`Reference ID: 39421 63
`
`

`

`
`
`Table l: Qualitative and Quantitative Composition of Linagliptin/Metformin HCl ER
`Coated Tablets, 2.5 mg/l 000 mg and 5 mg/1000 mg
`(fi'om M.2.3.P Quality overview summary)
`
`. 2
`
`1
`
`OPQ-XOPQ-TEM-0001v02 Effective Date: 13 Mar 2015
`
`Reference ID: 39421 63
`
`Reviewer’s Assessment: .
`
`.
`
`.9
`
`formulation, the SUPAC IR guidance (for solid oral
`s is an oral
`Since
`dosage forms) would not be applied The differences for the inactive ingredients between
`the two strengths are considered minor. The Applicant submitted two in vivo '
`Bioequivalcnce (BE) studies (study# 1288.9 for 5 mg/IOOO mg and SW 1288. 11 for
`2.5 mg/IOOO mg), which are under reviewing by the Office ofClinical Pharmacology
`.-No Biowaiver
`-
`'
`'
`
`

`

`}.a- _QUALITY ASSESSMENT
`7
`
`2. The pronosed in vitro dissolution method
`
`11) In vitro dissolution method develonment
`
`
`
`.22
`
`OPQ-XOPQ-TEM—0001v02 Effective Date: 13 Mar 2015
`
`Reference ID: 39421 63
`
`

`

`
`
`OPQ-XOPQ-TEM—OOO] v02 Effective Date: 13 Mar 2015
`
`23
`
`Reference ID: 39421 63
`
`

`

`QUALITY ASSESSMENT
`
`(b) (4)
`
`Reviewer’s Assessment:
`
`The dissolution method development with the following conditions and the related data
`has been evaluated to support the proposed dissolution method and acceptance criteria
`(see M.3.2.P.5.6 Justification of Dissolution Specification for details):
`BCS classification of linagliptin and metformin HCl, including solubility and
`permeability;
`Selection of apparatus, rotation speed, and dissolution medium for linagliptin and
`metformin HCl release;
`Discriminating pow er of the method, including the manufacturing variables (such
`mm)
`as
`
`(b) (4)
`
`
`
`The Biopharmaceutics review team considered the proposed dissolution QC method
`utilizes Apparatus l (baskets) at 100 {pm with dissolution medium of SGF without
`enzymes at pH 1.2 is suitable for the proposed drug product, Linaglipin/Metformin HCl
`Extended-Release Fixed Dose Combination (ER—FDC) Tablets, both strengths as 2.5
`m_/1000 mg and 5 mg/lOOO m_.
`
`12! In vitro dissolution method procedure and analytical method validation
`
`The analytical procedure for dissolution of linagliptin of drug product (Method# 929888)
`was submitted in M.3.2.P.5.2, effective on 12/02/2014.
`
`The analytical procedure for dissolution of metformin HCl of drug product (Method#
`929887) was submitted in M.3.2.P.5.2, effective on 11/25/2014.
`
`The method validation report of dissolution of linagliptin of drug product and related data
`(Study# 15-059-01) was submitted in M.3.2.P.5.3, which were validated in terms of
`linearity, accuracy, precision, specificity, and robustness, summarized in Table 6.
`
`The method validation report of dissolution of metformin PIC] of drug product and
`related data (Study# 15-074-01) was submitted in M.3.2.P.5.3, which were validated in
`terms of linearity, accuracy, precision, specificity, and robustness, summarized in Table
`7.
`
`24
`
`OPQ—XOPQ-TEM-0001V02 Effective Date: 13 Mar 2015
`
`Reference ID: 39421 63
`
`

`

`QUALITY ASSESSMENT
`amen .
`
`Table 6: Dissolution method validation summary for Linagliptin of drug product
`(from M.3.2.P.5.2)
`
`Method of
`Determination
`
`Validation
`
`Parameter
`
`linearity
`Perfumed at 8
`C «relation eoeficient: l.000
`
`
`
`X. a
`l
`..
`I'o
`concentrations ROI??? Yinteseept of().07% (25 mg) and 0.03% (5 mg)
`
`
`
`m m 25022 (g 5 mg)
`Slope «349350.917 mV-sedug/mL(2.S mg) and
`
`
`osfmlinagli
`. pot '
`348971.454 mV-scc/ug’ml. (5 mg)
`
`
`
`Linearnnge fi'om 5°hto 12 “6(5 mg)and10%t0247 9%
`
`
`(25 mg) of linagliptin potency
`
`
`
`
`Ovetall average recovery of99% with
`Performed by analysing
`
`
`individual recorery rewlts ranging fimn 93.8%
`spiked placebo sample
`
`
`
`to 101.8%
`solutions in uiplicate at
`
`
`
`
`Overall average recovery of 101% with
`3:023:35, 80% and
`.
`.
`.
`‘
`.
`Io
`e 2.5 mg
`
`
`
`individual moiety malts ranging from
`5mm and approx.
`
`
`1005”” 1°14"
`2m. 80°.and1503.for
`
`
`the 5 mg strength ofthe
`Ovetall avenge recovery of 101% with
`
`
`individual Iecovery results ranyng from 99.3%
`11W SWIG 501"“
`
`
`to 103.9%
`concentration of
`
`
`
`linaglxptm'‘
`
`
`One batch ofeach
`
`Precision
`The RSD of the percent recoveties (0:12) should not be more
`
`
`
`(repeatability)
`strength was piepared
`than 6.0 96 at 30 mimics.
`
`
`
`
`“4‘6“ 12 ms by
`Results:
`2.5 mflSO mg: 2.6%
`
`
`
`
`
`lb! PW Mn“
`2.5 mg’lOOO 1113:4023
`5 mgi'IOOO mg:
`3.2 95
`
`
`One batch cinch
`The RSD (F12) shouldnot be more than 6.0 93 at 30 minutes
`
`
`
`for each analyst and theovuall RSD for all analysts (n=36)
`mength was prepared
`
`
`
`
`andnemd 12timeslry
`shouldnotbemmethanflOfi at30minntes.
`the proposed method
`
`
`2.5 mg/ 750 mg: RSI) = 11 S-o
`
`
`2.5 ins/1000 mg: RSD = 3.7 91:
`
`S mg’lOOO mg: RSD = 3.3 9'.
`
`
`2.5 mg! 750 mg: RSD = 3.3 ‘/o
`
`
`2.5 mg’looo mg: RSD = 4.5 %
`
`5 mg’lOOO mg: RSD = 2.0 9-;
`
`
`
`
`Evaluation if degradants
`In the chromatop'ams of the placebo solutions. dissolution
`
`
`
`mediaandCDlOOSSsohifionthenwerenodgnifieant
`ototheneleumpeaks
`
`
`
`interfaingpeakspresentintheretentwntimewindowof
`atesepatated fi'om
`
`
`
`linagliptin.
`linagliptin (dissolution
`
`
`
`media,plaoebo&
`
`metfoimin solution)
`
`
`
`2.5 mg’ 750 mg: RSD = 2.6 '6
`2.5 tog/1000 mg: RSD = 3.9 $3
`5 11130000 mg: RSD = 2 .9 91:
`
`,
`
`n
`
`25
`
`OPQ-XOPQ-TEM-0001v02 Effective Date: 13 Mar 2015
`
`Reference ID: 39421 63
`
`

`

`QUALITY ASSESSMENT
`
`Table 6: Dissolution method validation summary for Linagliptin of drug product
`(from M.3.2.P.5.2) Continued)
`
`Validation
`Parameter
`
`Method of
`Determination
`
`Results
`'
`
`
`
`
`
`
`Linagliptin retention time, peak area, peak efficiency and
`One chromatographic
`tailing factor are evaluated with tariations in column batch.
`method parameter was
`
`
`mobile phase composition detector wavelength. column
`varied at a time.
`
`
`temperature and flow rate. Ifsignificant performance
`Difierent column
`
`
`
`deviations are noted then a precautionary statement is in the
`batches were also used
`
`
`
`method.
`during the repeatabflity
`
`
`
`Results:
`8: reproducibility
`
`
`
`
` studies.
`Shifts in performance were observed when the mobile phase
`composition was changed.
`
`
`Twelve tablets were
`The difi‘erence between the average results obtained at 30
`
`
`
`minutes for the manual and automatic sampling should not be
`analyzed by the
`
`
`
`
`proposed method and
`more than 5 %,
`
`sampled at 30 minutes.
`
`2.5 rug/10001115
`30 minutes
`
`
`Manual:
`98.] 9/.
`
`(Analyst 1)
`Manual:
`(Analyst 2)
`
`Automated;
`97.] V0
`
`Max. difl'(%).: 17.
`
`
`‘Ihe difi’erence between the average recovery result of
`One repeatability sanqale
`
`
`solution (2.5 mg/1000
`Linagliptin ofthe filtered and centrifuged sample solutions
`
`
`
`should not be more than 2.0 % (absolute).
`mg and 5 mg.” 000 mg
`
`
`strength) were analyzed
`
`
`Results:
`Three separate W‘s
`
`
`
`The difi'erence between the average teem-cry result of
`°f “Ch “Wk 591m”
`
`
`
`linagliptin of the filtered and centrifuged sample solutions
`were collected usmg the
`
`
`
`same marl“! 51‘“ i
`was l % at maximum.
`non-filtered aliquots
`
`were also obtained by
`
`centrifugation.
`
`
`
`969 "/o
`
`Validation
`Parameter
`
`
`
`Method of
`Determination
`
`
`
`_
`Standard.
`
`Sample:
`
`A working standard
`Robustness
`The standard and sample solutions are considered stable for a
`solution and dissolution
`(stability of
`specified time as stored if recovery is within 98 % to 102 "/3
`
`
`
`
`sample were stored at
`analytical
`of the initial result.
`
`
`
`
`ambient and refrigerated
`solutions)
`Results:
`
`
`
`
`conditions and
`0,
`.
`.
`
`comma to {mm},
`Clear flask, ambient. 99.3 - 99.9 ,o
`
`
`
`“wand standards at
`Refngerated: 99.4 — 100.0 “A:
`
`
`
`various time points up to
`Clear flask. ambient: 93.9 — 98.6 %
`
`
`6 days.
`Refiigerated: 98.5 _ 99.7 9;.
`
`
`
`The standard solution is stable for 6 days when stored under
`
`ambient laboratory or refrigerated conditions.
`The sample solution is considered stable for a specified time
`
`
`as stored if the percent recovery is within 2.0 % (absolute) of
`the initial result.
`Results:
`
`
`
`
`The maximum difi'erence in percent recovery observed versus
`the initial result after storage for up to 6 days is 1.7 %
`
`(ambient) and 1.4 % (refrigerated). The sample solution is
`stable for 6 days when stored under ambient laboratory or
`refrigerated conditions.
`
`
`26
`
`OPQ-XOPQ-TEM-0001v02 Effective Date: 13 Mar 2015
`
`Reference ID: 39421 63
`
`

`

`QUALITY ASSESSMENT
`
`Table 7: Dissolution method validation summary for Metformin HCl of drug product
`(from M. 3. 2. P 5. 2)
`
`Performed at 7
`communion; from
`approxJOfio (750 mg)
`up to 1209’. (1000 mg)
`of metformin potency
`
`Perfumed by analysing
`spiked placebo sample
`solutions in triplicate at
`approx. 30%. 80% and
`140% of the nominal
`sample solution
`concentration of
`metformin
`
`Correlation coeficieor. 1.000
`
`Y-intercept of 1.2 "/9 (750 mg) and 1.1%(1000 mg)
`Slope of 1,417,988.120 mV-sec/ug/mL (750 mg) and
`1,420513832 mV—sec/pg‘mL (1000 mg)
`'
`Lmearmge from 10'(no 160% (750 mg)znd 7.5 “no
`120 96 (1000 mg) of incrformin potency
`
`Overall average recovery of 103.4 9!. with
`individual recovery results ranging fi'om
`100.] 9510 106.0 5”.
`
`Overall mange recotuy of 102.4%wil11
`indi‘.idual recovery results ranging from
`100195101016 ":6
`
`Overall axenge recovery of 102. 7 °owith
`indiudual recovery results ranging fiom
`100.7 9'. to 105.3%
`
`the proposedmethod
`
`Precision
`(repeatability)
`
`One batch ofeach
`strmgth was prepared
`and tested 12 times by
`
`and tested 12 times by
`
`The RSD of the percent recoveries (F12) should not be more
`than 6.0 9. at 2 hows, 4 houn and 12 hours.
`
`Results:
`2.5 mgnso mg:
`2.5 rug/1000 mg:
`5mg’1000mg:
`
`Mm
`1.7 94.
`1.6 9'6
`1.1%
`
`5m 121121111
`1.1 9'.
`0.9 W.
`1.] '16
`1.2 '11
`1.1%
`1.2%
`
`The RSD (11:12) shouldnot bemorethan 6.0% a: 2 hours. 4
`hours and 12 hours for web analyst and the overall RSD for
`all analysts (11:36) should not be more than 6.0 We at 2 home,
`4 hours and 12 hours.
`
`2.5 mgHSO mg;
`2.5 mgIIOOOmg.
`5 tug/1000 mg:
`
`2.5 mgflSO mg.
`2.5 mtg/1000111:
`5 mg’lOOO mg;
`
`2.5 tug/750 mg:
`2.5 mg‘lOOO mg:
`Slug/1000133:
`
`1119.213 4hom12hours
`1.4 '3”.
`1.2 °Io
`1.0 “'5
`0.9 ”A
`1.0 “f.
`0.7 $5
`1.2 '3';
`1.0 ‘3.
`0.9 9’.
`
`2.1mm 11mm: 12.1mm
`2.6 “n
`1.9 °-o
`1.2 316
`1.8 ‘1.
`1.4 '3’»
`1.4 “-1
`22 % 2.5 '/o
`4.6 9'.“
`
`2119an Show 1.1mm
`2.6 °.-.
`1.6 9‘.
`1.9 '76
`1.6 93
`1.2 °.'.
`1.9 9/.
`2.1 °/o
`2.1 W.
`3.1 ‘3’.
`
`Reference ID: 39421 63
`
`OPQ-XOPQ-TEM-OOOIVOZ Effective Date: 13 Mar 2015
`
`

`

` mung-mum
`
`QUALITY ASSESSMENT
`
`Tabie 7: Dissolution method validation summary for Metformin HCl of drug product
`(from M.3.2.P.5.2) (Continued)
`
`lathe Wyn: offi: placebo solution dissolulinn
`madiaandmflfm impudb'fidmemnosipiicm
`.
`.
`wufuingpeizmhhmfimmbwof
`
`Ex-dmtion if degradanb
`ow ofll‘ulcvan peaks
`are separated Emu
`new (dissolution
`uodu, plxo‘ao,
`new 5: mdfolmin
`impmxy E solution)
`
`Mufcmhnmoefimlgukmpeakdfichuqmd
`bile; factor are evaluated with tuition: in colmm 311d.
`
`Wndfimme. Iisignificmpuimnmoe
`hanmmnflndflamamufimrymtisinth
`mahod
`Remit:
`Shfis' inpufioxmnuuuo’osmuln‘hmthzmhflephzu
`catamaran" midweek mohaglhmdnnged
`Ihe difiuzncebmun the mung! Icahn ('5’- digit-d)
`Mulbmlhammduhflmbrhmzlmd
`rhficsmpiigshmidmbemflznfk
`
`Imhtu‘fletsm
`mlyudibyth
`mosedwodmd
`mieda2hmn, 4
`human! 12 boils.
`
`36.8% 57.9 ‘33
`
`97.3 9‘o
`
`One repeatability sample
`whim (2.5 1139750 mg
`and S mf'lGDO n15
`stun) we nub-ad.
`Thai mm aliquot:
`
`Rails:
`No difi‘umbmenfiu mgmurynsultof
`Wd‘hwudmifimduwk salmon;
`
`mso‘xen'ld.
`
`1hr.
`38.1 '13
`
`59.8% 100.7 ‘3".
`
`Liana}:
`(Am-115* 1)
`Manual:
`(H.751 2)
`58.4 'A 97.4 5’.
`37.5 3":
`$11!de
`25"
`3?".
`M:x.difl'(!’-).: ”’3
`The (£53chth fin avenge may usvh of
`mutfiamlin offln MarlWSW solution:
`should nothmhn2$3 (ahead-h).
`
`28
`
`OPQ-XOPQ-TEM-0001v02 Effective Date: 13 Mar 2015
`
`Reference ID: 39421 63
`
`

`

`I... W-..”
`may: ..
`,
`QUALITY ASSESSMENT
`
`Table 7: Dissolution method validation summary for Metformin HCl of drug product
`(from M.3.2.P.5.2) (Continued)
`Method of
`Determination
`
`'alidatiox
`Pan-mt“
`
`Robustness
`" 'of
`
`
`
`
`
`
`
`nemwsmplemncmdéuedflabhfaa
`Awoxiingmm'ud
`:pedfiedflmaasmuiifncmmyisnithmflfibao 182%
`soixtfionanddissohficu
`oftheinifialrualt.
`sanpleuuemedat
`
`
`mbiutandnfigmmd Remit:
`
`
`Nadia”? -,-
`Standard: mummm 993-10152;
`
`
`
`““9”“ aw
`Refrigerated; 99.9 - 101.4 --2
`
`med :tznduxi; at
`
`
`immunepomzupm Sample: mmm‘m 934-10119.
`
`
`
`
`
`5 dm
`Remand; 93.7 — 192.5 a;
`
`The Mafia: stable fwédzyzwhnstmedundx
`
`ambient laboratory ornfiigcaw-d condition.
`
`The sample solution is mixedsfzblefaa spedfiedtilm
`3:. stored ifthe percent leeway i: within'lo 9": {2150th of
`fie initid insult.
`
`Remain:
`The maxinmmdiifirm inpercemucmuy obsennd “am:
`
`fiefifialnmhafiu‘WhimtoSdaysi: 3.1%
`
`(ambiem) and 1.5 '1 (refiigeztzd) for the 2.5 mgqfifl mg
`
`staph and 1.6 ‘16 (ulna?) 1d 2.0 ‘5! (digested) fertile
`
`5 mg"1003 mg strength
`
`The sample solution is stable for 6 thy: when stared index
`Hashim? Elana-nary ornfi-iguzhé «auditing.
`
`
`
`Reviewer’s Assessment:
`
`reports are considered adequate.
`
`The submitted in vitro dissolution method procedure and analytical method validation
`
`3. The in vitro dissolution data and specifications
`
`One biobatch of each strength of drug product was employed in the in vitro dissolution
`testing by using the proposed QC method [Apparatus 1 {baskets} at 100 {pm with
`dissolution medium of SGF without enzmes at pH 1.2 |. The batch information is
`summarized in Table 8 below (from M.3.2.P.2 Pharmaceutical Development
`Comparative Dissolution, M.3.2.P.2 Clinical Trial Formulations and Batches, and
`M.3.2.P.5.6 Justification of Dissolution Specification). The mean and individual data of
`biobatch drug product (