214622orig1s000...drug substance soumya mitra ali al hakim drug product rajiv agarwal anamitro...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

214622Orig1s000

PRODUCT QUALITY REVIEW(S)

NDA OPQ Review and Evaluation NDA 214622[TRADENAME] (infigratinib)

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FDA assessment is indicated in blue colored fonts

NDA OPQ Review and Evaluation

Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant, which do not necessarily

reflect the positions of the FDA.NDA 214622Review # 01

OPQ RECOMMENDATION: APPROVAL

Drug Substance Retest Period:

A retest period of months is supported for infigratinib drug substance when stored

FDA Assessment: Retest date of months may be granted when stored at the proposed storage conditions

Drug Product Expiration Dating Period:

An initial shelf life of 24 months will be applied to the drug product packaged in blisters when stored under the following conditions:

Store at USP controlled room temperature conditions, 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C and 30°C (59°F and 86⁰F)

FDA Assessment: An expiration dating period of 24 months may be granted when stored at the proposed storage conditions.

Drug Name/Dosage Form Infigratinib CapsulesStrength 25 and 100 mgRoute of Administration OralRx/OTC Dispensed RxIndication Treatment of adults with previously treated, unresectable,

locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements.

Applicant QED Therapeutics, Inc. US agent, if applicable N/A

[FDA will complete these sections.]

Reference ID: 4763235

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Submit Date(s) September 20, 2020Received Date(s) September 20, 2020PDUFA Goal Date May 29, 2021Division/Office Division of Oncology 3/Office of Oncologic DiseasesReview Completion Date March 21, 2021Established Name Infigratinib(Proposed) Trade Name (pending approval)Pharmacologic Class Kinase inhibitorRecommendation on Regulatory Action

Approval

SUBMISSION(S) REVIEWED

DOCUMENT DATE

DISCIPLINE(S) AFFECTED

Original NDA 09/20/2020 CMCAmendment 10/22/2020 DP, Biopharmaceutics

Labeling 11/05/2020 DPAmendment and Labeling 11/23/2020 Biopharmaceutics, DP

Amendment 12/22/2020 BiopharmaceuticsAmendment 12/29/2020 DP

Amendment and Labeling 2/4/2021 OPMA, DPAmendment 2/19/2021 DSAmendment 03/05/2021 OPMA

Quality Review TeamDISCIPLINE PRIMARY REVIEWER SECONDARY REVIEWER

Drug Substance Soumya Mitra Ali Al HakimDrug Product Rajiv Agarwal Anamitro Banerjee

Process and Facility Diane Goll Rakhi ShahMicrobiology Diane Goll Rakhi Shah

Biopharmaceutics Gerlie Gieser Banu ZolnikRegulatory Business Process

ManagerAnita Brown

Application Technical Lead Xing WangEnvironmental Raanan Bloom

ORBIS Partner Agency Quality Review Team (To be redacted for FOIA)Agency PRIMARY

REVIEWERSECONDARY REVIEWER

BIOPHARMA REVIEWER

HC Canada


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All FDA assessment is indicated in colored fonts: Executive Summary, Drug Substance, Drug Product, Environmental Assessment, labeling, Process, Facility, Biopharmaceutics, and Microbiology.

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TGA Australia

(Observer)

N/A N/A N/A

RELATED/SUPPORTING DOCUMENTS

DMFs:[Applicant will complete] [FDA will complete]

DMF # Type Holder Item Referenced Status CommentsIII Adequate Active;

supports several approved A/NDA’s

III Adequate Active; supports several approved A/NDA’s

III Adequate Active; supports several approved A/NDA’s

Other Documents: IND, RLD, or sister applications

DOCUMENT APPLICATION NUMBER DESCRIPTION

IND 104187 Infigratinib IND

CONSULTS[FDA will complete this section.]

None


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TABLE OF CONTENTS

1. EXECUTIVE SUMMARY ................................................................62. APPLICATION BACKGROUND ....................................................63. SUMMARY OF CMC SPECIFIC PRESUBMISSION AGREEMENTS ............................................................................................84. ENVIRONMENTAL ASSESSMENT...............................................85. FACILITIES .......................................................................................86. DRUG SUBSTANCE........................................................................11

a. GENERAL DESCRIPTION AND STRUCTURE.............................................11b. DRUG SUBSTANCE MANUFACTURING PROCESS ..................................12

i. Starting Materials ............................................................................................16c. CHARACTERIZATION OF DRUG SUBSTANCE AND IMPURITIES ........18d. CONTROL OF DRUG SUBSTANCE...............................................................20

i. Key Analytical Methods and Summary of Validation Data.............................23ii. Summary of batch data ....................................................................................28

e. CONTAINER CLOSURE SYSTEM .................................................................31f. STABILITY DATA............................................................................................31R. REGIONAL INFORMATION...........................................................................34

7. DRUG PRODUCT............................................................................34a. DRUG PRODUCT DESCRIPTION AND COMPOSITION ............................34b. DRUG PRODUCT MANUFACTURING PROCESS.......................................37c. EXCIPIENTS .....................................................................................................43d. CONTROL OF DRUG PRODUCT ...................................................................45

i. Key Analytical Methods and Summary of Validation Data.............................48ii. Summary of batch data ....................................................................................57

e. CONTAINER CLOSURE SYSTEM .................................................................65f. STABILITY........................................................................................................65R. REGIONAL INFORMATION...........................................................................69

8. BIOPHARMACEUTICS .................................................................69a. BCS CLASSIFICATION ...................................................................................69b. DISSOLUTION TEST .......................................................................................69


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c. BRIDGING THROUGHOUT DRUG PRODUCT DEVELOPMENT (FORMULATION, PROCESS, OR SITE CHANGE)................................................73d. BIOWAIVER REQUEST ..................................................................................76e. DATA TO SUPPORT IVIVC AND/OR PBBM MODELING, IF APPLICABLE. ............................................................................................................77

9. LABELING .......................................................................................78Final Risk Assessments ...............................................................................79Recommendation Page................................................................................83


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Evaluation of the Quality Information[Applicant to provide link to the data in m3 sections as appropriate]

DIFFERENCES IN M3 MODULE IN SUBMISSIONS TO DIFFERENT AGENCIES

# TGA (Australia) HC (Canada) FDA (US)3.2.S.2.1 QED is not

included in the list of facilities.

QED is not included in the list of facilities.


QED listed as a site for “Final QA Release and Quality Oversight”

3.2.P.3.1 QED is not included in the list of facilities.



QED listed as a site for “Final QA Release and Quality Oversight”

1. EXECUTIVE SUMMARY

[FDA ATL will complete this section.]Infigratinib is a kinase inhibitor of FGFR1-3. Infigratinib drug substance is a white to off-white powder, non-hygroscopic, melting temperature range 190-198°C. Infigratinib phosphate is isolated as crystalline form, that has been used throughout all development studies. Phosphate Content %, correlating to a monophosphate. Infigratinib phosphate drug substance is manufactured in

process comprised of three starting materials and five intermediates.

The commercial batch size of infigratinib phosphate drug substance is approximately kg. The drug substance specifications are acceptable. Method validations are adequate. Trends in specified impurities/degradants and were observed during drug substance stability study. A retest period of -month may be granted when stored in proposed storage conditions.

Infigratinib capsules, 25 mg and 100 mg, contain infigratinib phosphate equivalent to 25 and 100 mg infigratinib free base. All excipient/components meet the current USP requirements and are within the levels in FDA’s Inactive Ingredient Database. The capsule shell is made from gelatin and provided specifications deemed adequate. A BSE/TSE statement is provided in the cross referenced DMF and is adequate. The drug product specifications are acceptable. Method validations are adequate. The Applicant intends to launch 4 commercial presentations for infigratinib capsules. All presentations are blister packs supporting: 50, 75, 100, and 125 mg daily doses. The 25 and 100 mg capsules will be used to support all configurations. Blister packs of infigratinib capsules, 25 and 100 mg, were packaged inside a cardboard box. packaging meets requirements . Trends in specified degradants and


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were observed during drug product stability study. A 24-month expiration dating period may be granted when “Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F)”. Labeling comments have been conveyed to OND and the applicant during labeling meeting.

The drug product has with % API. The commercial batch size is kg ( capsules) for 25 mg and kg ( capsules) for 100 mg capsules

and no scale-up is proposed. The manufacturing process includes

. The drug product facility at is approved based on PAI. All other facilities are approved based on

compliance history and relevant manufacturing experience.

A BCS-IV (low solubility, low permeability) designation may be a more appropriate classification for infigratinib (rather than BCS-II). The proposed dissolution method and acceptance criterion (Q = % at 30 min) are acceptable. In vivo PK data (and in vitro dissolution profile data) are available for the final proposed commercial formulation (FMI-IV) as well as all other earlier developmental clinical service formulation and final marketing image formulations (CSF, FMI-I, FMI-II, and FMI-III) of infigratinib capsules. FMI-IV (as well as FMI-I and FMI-III) capsules were used in the pivotal clinical trial (Study CBGJ398X2204). Adequate in vitro dissolution profile (and/or in vivo PK) data were provided to establish the overall bridge among these three formulations.

In conclusion, OPQ recommends APPROVAL of NDA 214622.

Life Cycle Considerations:None

2. APPLICATION BACKGROUNDApplication Background and Regulatory History

Activity Date SummaryType C (CMC only) April 17, 2019 The following primary topics were addressed:

1. Justification for selection of regulatory starting materials. Information pertaining to the justification of starting materials along with commercial specifications, analytical procedures and batch analyses data for starting materials is provided in Section 3.2.S.2.3.

2. Suitability of the drug substance specification, including particle size control. Detailed justifications for the acceptance criteria applied to each test attribute in the drug substance specification are presented in Section 3.2.S.4.5.

3. FDA expectations for the provision of registration stability data in the initial NDA. The Applicant has provided at least 12 months of data from drug


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Activity Date Summarysubstance and drug product registration stability batches as presented in Sections 3.2.S.7,1 and 3.2.P.8.1, respectively.

4. Biopharmaceutics requirements and recommendations related to changes in manufacturing site(s) and/or changes to drug product formulation. A comprehensive presentation of formulation development and manufacturing process development is provided across Sections 3.2.P.2.2 and 3.2.P.2.3. In addition, the dissolution method development report is included in 3.2.R.2. Together, these documents present comparative in vivo and in vitro assessments following changes to formulation and (manufacturing) process, as applicable.

Fast Track Designation

September 10, 2019

Fast Track Designation was granted for treatment of first-line adult patients with unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or translocations to demonstrate clinically meaningful and statistically robust improvement in overall survival compared to cisplatin and gemcitabine.

Orphan Drug Designation

September 11, 2019

Orphan drug designation was granted for the treatment of cholangiocarcinoma.

Type C, (CMC only)

April 8, 2020 The following primary topics were addressed:1. Suitability of the proposed commercial release and

stability specifications for infigratinib drug substance and drug product. Justifications for the commercial criteria are presented in Sections 3.2.S.4.5 and 3.2.P.5.6. Information on safety qualification for specified impurities (exceeding the ICH qualification threshold) is provided in Section 3.2.S.3.2.

2. Suitability of the intended commercial dissolution procedure and the corresponding manufacturing variation studies used to challenge the method. Detailed information pertaining to dissolution method development and formulation/manufacturing variation studies are presented in the dissolution method development report located in 3.2.R.2. The Agency recommended specific studies related to variation in and as well as

particle size. These studies are included in the method development report.

Proprietary Name request

June 11, 2020 Submission of proprietary name request for infigratinib

Type B, Pre-NDA July 28, 2020 The content and format of the planned submission of a New Drug Application (NDA) for infigratinib for the treatment of patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or other arrangements. CMC discussions and agreements included:


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Activity Date Summary FDA did not object to the proposed Table of

Contents for the planned NDA including proposals for Module 2.3 and Module 3 format and structure.

The submission of

will not be included in the initial application.

3. SUMMARY OF CMC SPECIFIC PRESUBMISSION AGREEMENTS

The Applicant’s Position:

Refer to Section 2 for a comprehensive presentation of CMC-specific regulatory activity.

The FDA’s Assessment: Consistent with FDA's records

4. ENVIRONMENTAL ASSESSMENT


A claim for categorical exclusion from conducting an environmental impact statement or environmental assessment (EA) is made under 21 Code of Federal Regulations (CFR) Section 25.31 on the basis that estimated concentration of the active moiety into the aquatic environment is less than 1 part per billion (ppb). A statement of “no extraordinary circumstances” is provided.

The FDA’s Assessment: Adequate

The applicant has submitted a claim of categorical exclusion under 25.31(b), including a statement of “no extraordinary circumstances.” Information is provided on production levels for sale: approximately kg/year is produced for direct use as the active moiety, infigratinib ( kg of API infigratinib phosphate). No extraordinary circumstances are noted. This very low production level is considered as “de minimus” and, as such, a full EA Team review is not required The claim of categorical exclusion is adequate.


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R. REGIONAL INFORMATION

Comparability Protocols for post-approval changes (if applicable)

No comparability protocols are included in the initial NDA submission. Components provided in 3.2.R (Regional Information) include drug product batch records (EBRs and MBR) submitted to Section 3.2.R.1 and a dissolution method development report (MDR) and method validations package submitted to Section 3.2.R.2.

The FDA’s Assessment: Not Applicable

[FDA will complete this section.]

8. BIOPHARMACEUTICS

a. BCS CLASSIFICATION

Applicant to fill: FDA assessment (FDA to fill):BCS Classification: BCS II Not acceptable

While infigratinib exhibits solubility of >1 mg/mL in the gastric pH range, measured solubility in aqueous media at at physiologic pH (i.e. 6.8) is less than 1 µg/mL. Therefore, infigratinib solubility is classified as "low" according to the Biopharmaceutics Classification System (BCS). The permeability of infigratinib has been investigated in multiple studies including, but not limited to, in vitro assessments in Caco-2 cells and in silico modeling using an In Vitro Dissolution Absorption System 2 (IDAS2) (refer to Section 2.6.4). In aggregate, the available data on permeability, transporter efflux, and oral bioavailability demonstrate that infigratinib exhibits moderate to high permeability. Based on a holistic assessment of the relevant data, a designation of BCS class II is assigned with consideration for the measured aqueous solubility combined with the available data on permeability and oral bioavailability. Additional information regarding the Absorption Systems LLC modelling can be found in Section 3.2.R.2.

FDA Comments: Assessment: . Based on the in vitro and in vivo data, infigratinib does not meet the criteria established for a high solubility and/or high permeability drug substance. A BCS-IV (low solubility, low permeability) designation is more appropriate classification for infigratinib (rather than BCS-II).

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FDA agrees with the Applicant that per BCS criteria, infigratinib is a low solubility drug substance. Based on the equilibrium solubility data in Table 1 of 3.2.R.2 Dissolution Method Development Report/DMDR, infigratinib solubility at 37°C in pH 1 and pH 2 hydrochloric acid media is less/lower than 1 mg/mL, and up to 1.7 mg/mL in pH 3 and pH 4.5 buffer media. The solubility in pH 6.8 buffer media was reported to be not higher than 0.0005 mg/mL. Kinetic solubility profile data of infigratinib in various pH media at 37°C (over a 4-hour test duration) were also provided for the API (but not for

because per the Applicant, only had been successfully isolated for infigratinib phosphate); refer to the Applicant’s response to FDA information request (SN-8). In SN-12, the Applicant attributed the significantly lower infigratinib solubility values at later sampling time points in low pH media containing hydrochloric acid to the presence of (refer to Table 5 of the IR Response). The Applicant explained that such is not consequential to dissolution testing as the measured equilibrium solubility values were still higher than needed to dissolve the API content of the 25 mg and 100 mg capsules, as shown in ‘Figure a’ below where there is no observed apparent time-dependent decrease in dissolution profiles when using

and 0.01N HCl.

Permeability: Low (Moderate, at best)The proposed labeling states: “After a single oral dose of radiolabeled infigratinib, approximately 77% of the dose was recovered in feces (3.4% as unchanged) and 7.2% in urine (1.9% as unchanged).”. Therefore, since only 80.8% (i.e., <85%) of the administered dose of infigratinib is systemically absorbed [over 11 days post-dosing], strictly speaking, it does not meet the criteria for a high permeability drug substance.Furthermore, based on the results of the in vitro Caco-2 permeability study, infigratinib 1 µM, 4 µM, and 22 µM exhibited apparent permeability values closer to (albeit, slightly higher than) that measured for the low permeability marker (mannitol), i.e., 1.7, 2.3, 1.6 x 10-6 cm/sec, respectively versus 1.13 x 10-6 cm/sec than to that measured for the high permeability marker (propranolol; 13 x 10-6 cm/sec). Note that the reported Cmax,ss of infigratinib in cholangiocarcinoma patients is 0.59 µM (322 ng/mL), and the solubility of infigratinib in FaSSIF is 48.6 µM (0.0272 mg/mL). (2) Additionally, infigratinib is a substrate of drug efflux transporters (e.g., P-glycoprotein). Therefore, based on overall in vitro results alone, FDA conservatively classifies infigratinib as a “low permeability” drug substance.

Dissolution: Not Rapid Across the Physiologic pH RangeFigure 2 of the DMDR shows that the 25 mg and 100 mg infigratinib capsules exhibit rapid to very rapid dissolution in 0.01N HCl

.

b. DISSOLUTION TEST


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USP Apparatus

Paddle Rotation Speed

MediumVolume

Temperature Medium Acceptance Criterion

I (Baskets) 100 rpm 900 mL 37.0 °C 0.01 N HCl

Q= % of Label Claim at 30 minutes


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d. Justification for selection of the acceptance criteria (or criterion)Applicant to insert multipoint dissolution profile in a graphical format from clinical/PK and primary registration batches figure(s) here:Overlays by Formulation – 25 mg

Overlays by Formulation – 100 mg

Applicant’s comments:To determine the appropriate dissolution acceptance criterion, a failure assessment was performed using representative dissolution data from 25 and 100 mg capsules used in pivotal study CBGJ398X2204 across three formulations (i.e. FMI I, FMI III and FMI IV).

The FMI batches analyzed (X3360813 and X3370813) were shown to exhibit comparable in-vivo exposure to FMI III and FMI IV batches (also presented herein). Thus, a Q =


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% acceptance criterion set at a time point minutes would risk failure of batches demonstrated to exhibit acceptable in vivo performanceBased on the available data, a single-point dissolution acceptance criterion of Q = % in 30 minutes is proposed. Once the Q value is formally established as part of the NDA review process, the dissolution test will be a staged test of three levels following the guidance in USP <1092> and USP <711>

FDA Comment: Assessment: The proposed single-point dissolution acceptance criterion (Q = % at 30 min) is acceptable.

Note: The 100 mg (but not the 25 mg) strength of FMI-I contains the same excipients, as well as the same total excipients load/total capsule fill weight as FMI-II, FMI-III, and FMI-IV. Additionally, as shown in Table 23 below (unlike CSF), all four FMI formulations were/are manufactured using process. Thus, to explore the establishment of a clinically relevant dissolution acceptance criterion (and to assess the adequacy of the proposed dissolution method’s discriminating power for changes/differences in the drug product’s critical quality attributes), this Reviewer decided to focus on the in vitro dissolution profile data provided for the 100 mg strength FMI formulations.

Thus, considering only the in vitro and in vivo data of the 100 mg strength of the four FMI formulations) in updated ‘Figure d’ reproduced below, the proposed dissolution tolerance limit (Q = % at 30 min) is deemed acceptable because it accommodates the dissolution data at 30 min of the 100 mg FMI-I lot that exhibited rapid (>85%) dissolution at 30 min and showed comparable PK to the very rapidly dissolving 100 mg FMI-III and FMI-IV lots.

That the FMI-I’s 100 mg

capsule exhibited rapid instead of very rapid dissolution is not anticipated to result in lower efficacy because per the Clinical Pharmacology Reviewer, the cumulative AUCactivity of FMI-I (administered as 25 mg + 100 mg capsules to healthy subjects) was


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within 20% of those produced by FMI-II, FMI-III, and FMI-IV capsules, as shown in Figures 5 and 6 of the IR Response in SN-15.

Updated Figure d

Updated ‘Figure d’ Source: IR Response (SN-8)Reviewer Note: The 25 mg strength of FMI-I capsule contains unlike the 100 mg strength of FMI-I, and the 25 mg and 100 mg strengths of FMI-II, FMI-III, and FMI-IV Capsules.

Additionally, a single-point dissolution acceptance criterion is deemed reasonable for the routine QC testing of the proposed immediate release drug product for the following reasons: (i) As shown in ‘updated Figure d’ above, the 25 mg FMI-III and FMI-IV capsules used in the pivotal clinical trial (Study CBGJ398X2204) exhibited


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almost 100% dissolution at 15 minutes.

Per the FDA QT-IRT review of the Thorough QT (TQT) study results, the recommended dosage of infigratinib capsules (as FMI-III) did not result in a large mean increase (>20 msec) in QTc interval. Additionally, in the 1/28/2021 Midcycle Meeting with the Applicant, the FDA Office of Clinical Pharmacology is considering a Post-Marketing Requirement Study to determine a more tolerable (yet efficacious) dosage for infigratinib capsules (e.g., a starting dose of 100 mg daily, which is lower than the TQT studied dose).

Overall, this Reviewer concludes that the proposed acceptance criterion (‘Q = % at 30 min’) determined using the proposed dissolution method is a clinically relevant dissolution specification; every proposed commercial infigratinib formulation capsule lot that conforms to this specification is expected to exhibit comparable PK to the pivotal clinical lots. [However, it is emphasized that any subsequent formulation or other proposed major CMC change to the commercial infigratinib capsules would generally require conducting an in vivo BE study, consistent with current regulatory practice.]

Dissolution on StabilityOver up to 18 months of long-term storage, and over 6 months of accelerated storage [with addition of pepsin in the medium to resolve suspected gelatin crosslinking (Tier II testing), in some cases], the primary and supportive registration drug product lots conformed to the proposed dissolution acceptance criterion (Q = % at 30 min), with no apparent trends; refer to Reviewer Figure 1.


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Reviewer Figure 1. Mean Cumulative Dissolution Profile on Stability of the Proposed Commercial Infigratinib (FMI-IV) Capsules, 25 mg and 100 mg:

Clinical Lots and Primary/Supportive Stability Lots

Additional Comment regarding updated Figure d (not directly related to adequacy of the proposed dissolution acceptance criteria):Based on the in vitro dissolution profiles of the 100 mg strength FMI lots in updated ‘Figure d’ and the information provided in Table 23 below, this Reviewer concludes that the slower dissolution rate of FMI-I could be attributed mainly to used in this earlier developmental formulation, as compared to FMI-II, FMI-III and FMI-IV (

. Thus, it can be inferred from updated ‘Figure d’ that the proposed dissolution method has limited potential to discriminate infigratinib capsule lots with differences in API particle size (i.e., API). In the case of the 25 mg strength lots in updated ‘Figure d’, this Reviewer determines that the substantially lower dissolution profile of FMI-I compared to FMI-II, FMI-III, and FMI-IV could be attributed to the combined overall/net effects of the known CMC differences of the FMI-I vs. FMIs -II, III, IV, i.e., including not only use of drug substance that is

, but also higher capsule fill weight, lower percentage of etc., and presence of . Additionally, when considering only the 25 mg lots of FMI- II, III, and IV (three formulations that are qualitatively the same and with comparable PK) in updated Figure d,


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despite all three FMI formulations having used drug substance suggests that the observed slight difference in dissolution profiles is possibly due mainly to API PSD difference.

That there was no significant difference in the in vitro dissolution profiles of FMI-II and FMI-III/FMI-IV (for both 25 mg and 100 mg strengths; Figure d) is anticipated given the known qualitative composition sameness of these FMI formulations, as well as use of , and other formulation and manufacturing attribute similarities. In SN-15, the Applicant indicated that FMI-II (which showed almost superimposable dissolution profiles to FMI-III and FMI-IV) also produced cumulative AUCactivity in healthy subjects similar to FMI-III and FMI-IV. The Applicant’s relative cumulative AUCactivity conclusion is more in line with the known pharmaceutical quality attribute commonalities/similarities of FMI-II and FMI-III/FMI-IV. Additionally, based on Table 12 of the Applicant’s IR Response in SN-8, the dose-normalized infigratinib AUCinf of FMI-II was within 20% of that reported for FMI-III (a pivotal clinical trial formulation), and the lower-than-dose proportional increase from FMI-II could have been confounded by the higher FMI-II dosage administered in one study (i.e., 200 mg for FMI-II vs. 125 mg for all other formulations). Note that for assessments involving in vitro dissolution and in vivo PK comparisons, this Reviewer excluded the data from the earliest clinical formulation (CSF) as it is dissimilar from the later clinical formulations (especially the last three FMI’s) in terms of formulation composition and process attributes; refer to Table 23 below.

Note that the proposed drug substance QC specifications include: API particle size by Laser Diffraction (d90 of NMT µm), and XRPD testing for correct API form (

. Based on the in vitro data and in vivo cumulative AUCactivity information provided for FMI-II (and FMI-III and FMI-IV) capsules, the proposed API d90 of ‘NMT µm’ appears reasonable from a Biopharmaceutics perspective. As stated in Section 6c above, the proposed in-process QC specification for the drug substance (d90 NMT µm) was acceptable to the FDA Drug Substance Reviewer. Refer also the additional discussion regarding API Particle Size Distribution below.

Applicant to fill: FDA assessment:The dissolution method is discriminating for:

i) Particle size distribution (PSD) Not discrimitating AgreeIn accordance with recommendations received from the Agency during the Type C (CMC-specific) meeting held on April 8, 2020 (reference ID 4596142), variations in particle size were assessed for potential impact to dissolution performance. Link1: Refer to Section 3.2.R.2 (Figure 9).

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FDA Comment The referenced Figure 9 shows

Per the Applicant (SN-8), this apparent difference is an artifact of the experiment. Per the FDA Process Reviewer’s recommendation, particle size distribution testing will be added to the in-process QC specification (refer to IR Response in SN-20).

API particle size distribution is a CQA for low solubility drug substances like infigratinib. This Reviewer considers the proposed dissolution acceptance criterion (Q = % at 30 min) sufficient for identifying lots that are anticipated to produce drug exposures similar to those produced by the pivotal clinical trial formulations/drug products; for details, refer to Additional Comment regarding ‘Figure d’ in the previous section. Regarding the proposed drug substance particle size QC specification (d90 NMT µm), per discussion with Health Canada, the FDA requested the Applicant to specify controls for the input API material’s d10 and d50 (in addition to d90), or else provide justification. In SN-22, the Applicant proposed a three-tiered API PSD specification that appears consistent with the API PSD of the FMI-III and FMI-IV capsule lots that were used in the pivotal clinical trial. The final determination regarding the acceptability of the Applicant’s proposal is deferred to the Drug Substance Reviewer.

ii) Polymorph/solid state form Not applicable AgreeThe dissolution method was not evaluated for its sensitivity to potential changes in solid-state form of the API. The drug substance utilized

There are no conditions

determined where other known forms can occur in the presence of The drug substance batches manufactured to date using the intended commercial process have been concordant with Solid form confirmation is included as a test attribute in the drug substance release specification (see Section 3.2.S.4.1).

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FDA Comment:

The Applicant’s decision not to investigate the proposed dissolution method’s discriminating power for API polymorphic change is reasonable because the Drug Product Reviewer agrees with the Applicant that changes to input API polymorphic form are unlikely to occur during drug product manufacturing and storage. Note that per FDA request, the Applicant provided in SN-8 data to demonstrate API polymorphic form stability (by XRPD testing) at the level of the finished drug product (FMI-IV capsules, 25 mg and 100 mg) during at least 18 months of long-term storage.


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iii) Formulation variations Not discrimitating AgreeOf the excipients utilized in the intended commercial formulation, the and are considered the most likely components to impact dissolution. Therefore, in order to assess the sensitivity of the dissolution method with respect to variations in drug product composition,

were intentionally manufactured with either high or low and tested for

dissolution in comparison to a control(i.e. the commercial formulation).Link1: Refer to Section 3.2.R.2 (Figure 7 and Figure 8).

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FDA Comment:

It is noted that the target and variant capsule lots investigated were that were prepared at laboratory (instead of at least pilot) scale. Regardless, it

is important to point out that a slight decrease in dissolution was observed for the 25 mg capsule variants with

Greater variations in the levels could probably be anticipated to produce greater dissolution profile separations between target and variant lots.

could explain at least in part the less prominent impact of

level changes on dissolution rate of capsules as observed in this study.

iv) Manufacturing process variations Not discrimitating AgreeA DoE was executed

Dissolution samples were tested as n=12.

Link1: Refer to Section 3.2.R.2 (Figure 10).

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FDA Comment:

In SN-8, the Applicant indicated that the DoE lots included in referenced Figure 10 would all pass the proposed dissolution acceptance criterion, regardless of the applied variations in tested process parameters (within the ranges investigated in the DoE study).

v) Cross-linked Capsules: Discriminating Not applicable


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Crosslinking of the gelatin capsules has been observed for infigratinib drug product following 6 months of storage at the accelerated 40°C/75%RH. Although this behavior has not been observed at any other condition or timepoint to date, the results indicate that the method is appropriately sensitive to detect cross-linking occurring during storage. Link1: Refer to Section 3.2.R.2 (Figure 11).

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FDA Comment:

The proposed dissolution method’s ability to detect drug product lots that have undergone gelatin capsule cross-linking is not considered adequate and direct evidence of a dissolution method’s discriminating power for changes in critical quality attributes, but could possibly be considered as supportive of the proposed method’s stability-indicating potential because crosslinking can be caused by the capsule’s exposure to environmental factors such as heat, high/low humidity, light, oxidizing agents, etc. [In Section 6c above, the FDA Drug Substance Reviewer considers the drug substance as . In Section 7f, the Drug Product Reviewer indicated that at 6 months of accelerated stability testing, one supportive stability lot

required Tier II dissolution testing to resolve dissolution failure due to gelatin capsule cross-linking. It is possible that lowering the tolerance limit for (e.g., to NMT %) in the finished product QC specification could potentially lower the probability of Tier II dissolution testing. The acceptability of the proposed acceptance criterion for the finished product is deferred to the Drug Product Reviewer.] Of note, it is commonly believed that “incomplete in vitro drug release” due to gelatin capsule shell cross-linking does not necessarily have a clinically significant impact on the in vivo oral bioavailability of the drug product. To resolve dissolution failures reaching USP Stage 3 testing due to gelatin capsule crosslinking, Tier II dissolution testing (by adding the appropriate amount of a digestive enzyme, e.g., NMT 750,000 units pepsin/L water or medium with pH <6.8) is indicated. To address FDA recommendation, in SN-8, the Applicant incorporated Tier II testing in the Dissolution Standard Test Procedure.

vi) : Discriminating Not applicableAs presented in Section 3.2.P.2.3, the drug product manufacturing process was transferred from Novartis

in 2018 and performed using formulation FMI III. During the transfer exercise, dissolution failures were observed in the initial production lots. The corresponding investigation demonstrated that the commercial dissolution method has the ability to discriminate when the manufacturing process and/or formulation is outside of the acceptable ranges.Link1: Refer to Section 3.2.R.2 (Figure 12).

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FDA Comment:


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The presented scenario revolving around the need to optimize upon manufacturing

site transfer ( ) and suggest that the proposed dissolution method is sensitive to the collective

effects of these drug product manufacturing changes (i.e., facility & equipment). To clarify, no formulation or manufacturing process change occurred to the initial -manufactured capsule lots that failed dissolution testing. Note that the

contributed to the improved dissolution of the final proposed to-be-marketed formulation.

1The applicant to provide link to the appropriate section in the submission. FDA reviewer may update the link as needed.

c. BRIDGING THROUGHOUT DRUG PRODUCT DEVELOPMENT (FORMULATION, PROCESS, OR SITE CHANGE)

Table 23: Formulation Changes Throughout Drug Product DevelopmentFormulation CSF - 2010 FMI I – 2013 FMI II -2014 FMI III -2015 FMI IV –

2018/2019Manufacturing Location

Novartis

Strength (mg) and capsule size

1, 5, 25, 100 (all size 00)

25, 100 (both size 1)

25 (size 3), 100 (size 1), 125 (size 0)

25 (size 3), 100 (size 1), 125 (size 0)

25 (size 3), 100 (size 1)

Batch Size

N/A

Formulation ProcessInfigratinib phosphate Process


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Rationale/ Comment

Clinical Phase

Phase I Phase II&II Phase I (PK study)

Pivotal (Phase II)

Pivotal (Phase II)

1

N/A = not applicable

Table 24: Manufacturing Changes Throughout Drug Product DevelopmentCSF - 2010

FMI I – 2013

FMI II -2014

FMI III -2015

FMI IV1 - 2019

Comments

Manufacturing Location

Novartis FMI IV is the proposed commercial process

OperationMinor changes: no impact on DP quality

Major change

Same equipment FMI IV as FMI III

As above


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Minor change implemented from FMI III onwardsMajor change (as above) FMI III and IV used

. FMI I and II used

No changes

No changes

Change of equipment upon transfer to Functionally equivalent

1 FMI III was transferred to in Q3, 2018. During transfer the FMI III formulation was modified, resulting in FMI IV, due to differences in manufacturing equipment between (Section 3.2.P.2.2).

The infigratinib drug product manufacturing process has been developed, optimized, and scaled up over the course of approximately ten years with manufacturing located at three different facilities during development. The Applicant has manufactured clinical and primary stability batches at and plans to establish commercial production at this facility. The process includes

Initial clinical studies utilized in capsule formulation referred to as Clinical Service Form (CSF). Subsequently this was developed into

process referred to as Final Marketing Image (FMI I) and subsequent evolutions (FMI II, III and IV), all of which were based on

Link: Section 3.2.P.2.2 Page#: 6 - 17

Link:Section 3.2.P.2.3 Page#: 14 - 48


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process. The formulations; CSF, FMI I - FMI III were developed by Novartis and supplied by . Following the Applicant’s acquisition of the infigratinib development program from Novartis, the FMI III process was transferred from in Q3, 2018. However, during technology transfer of the FMI III process to differences between and

necessitated the development of a revised formulation, FMI IV, to replace FMI III. Comprehensive information pertaining to formulation development and manufacturing process development is provided in Section 3.2.P.2.2 and 3.2.P.2.3, respectively.



FormulationIn vivo PK data (and in vitro dissolution profile data) are available for the final proposed commercial formulation (FMI-IV) as well as all other earlier developmental clinical service formulation and final marketing image formulations (CSF, FMI-I, FMI-II, and FMI-III) of infigratinib capsules. FMI-IV (as well as FMI-I and FMI-III) capsules were used in the pivotal clinical trial (Study CBGJ398X2204). In the Applicant’s IR Response (SN-15), adequate in vitro dissolution profile (and/or in vivo PK) data were provided to establish the overall bridge among these three (pivotal clinical trial) formulations. Additionally, stability data were provided for three primary registration lots each and two supportive stability lots each of the 25 mg and 100 mg strengths of the FMI-IV formulation/capsule.

Drug Product Manufacturing Process/Site and API Manufacturing Process/SiteThe FMI-IV pivotal clinical lots and the primary/supporting stability lots were produced by the proposed commercial drug product manufacturer using the proposed commercial formulation and manufacturing process (

at a scale range within of the proposed commercial batch sizes ( K and K capsules, for 25 mg and 100 mg, respectively) and using drug substance lots produced by the proposed commercial API manufacturer ( ) using the final API manufacturing process (i.e., ). Appearance of capsules (clinical and primary/supportive stability lots final proposed to-be-marketed)Both the FMI-IV clinical and primary/supportive stability capsule lots included a

on the capsule body and a on the cap in place of specific imprinting whereas the final commercial image capsule excludes the and includes imprinting as a unique product identifier (“INFI 25 mg” and “INFI 100 mg”). In the Quality IR response in SN-20, the Applicant provided data showing that the pre-change (‘clinical’/stability) and post-change (commercial) drug products have almost superimposable dissolution profiles using the proposed QC dissolution method (as well as similar profiles in various pH buffer media), thereby demonstrating that the change in capsule image (i.e., removal of and incorporation of imprinting) did not


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significantly alter the dissolution profile of the proposed commercial drug product.

HDPE Bottle with Closure (clinical) blister (primary/supportive stability & final proposed TBM)The two manufactured drug product lots of each strength used in the pivotal clinical trial (as listed in Table 19 above) were packaged in HDPE bottles; one lot per strength was also packaged in blisters and used in supporting stability studies. To provide assurance/justification that the change in drug product packaging configuration after conducting the pivotal clinical trial will not impact the long-term stability of the final proposed to-be-marketed drug product, the Applicant provided additional data showing superimposable dissolution profiles of the 25 mg and 100 mg infigratinib capsule lots packaged in blister (for primary stability testing) versus its HDPE bottle packaged counterpart over up to 18 months of long-term and 6 months of accelerated stability testing; refer to Figure 2 and Figure 3 on page 25 of the IR Response in SN-8, or Reviewer Figure 2. Additionally, as indicated in Section 7a above, both HDPE bottle and blister packaging configurations are .

Reviewer Figure 2. Mean Cumulative Dissolution Profile on Stability of one Representative Lot each of 25 mg and 100 mg strengths of the Proposed

Commercial Infigratinib (FMI-IV) Capsules: HDPE Bottles (Clinical Packaging Configuration) versus Blister (Primary Registration Stability & Proposed

Commercial Packaging Configuration)


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In Table 4 of SN-12, the Applicant indicated that the 25 mg and 100 mg FMI-IV lots were 8 months to at least 22 months old at the time of used in the pivotal clinical trial (Study CBGJ398X2204), and a 25 mg lot of FMI-IV was 6 to 7 months old during use in PK Study QBGJ398-109.

d. BIOWAIVER REQUEST


Two capsule strengths (25 and 100 mg) are included in this application. Both strengths have been manufactured with the intended commercial process (i.e. FMI IV) and utilized in pivotal study CB GJ398X2204. Therefore, this NDA application does not contain a biowaiver request.



The recommended starting dose is 125 mg (one 100 mg capsule + one 25 mg capsule). To achieve the recommended 1st, 2nd, and 3rd dose reductions in Section 2.3, and for patients with moderate hepatic impairment in Section 2.4 of the proposed labeling, i.e., 100 mg, 75 mg, 50 mg, and 75 mg, respectively, administration of one 100 mg capsule or two to three 25 mg capsules is recommended. Thus, the proposed drug product will be commercially supplied in four (21-day dose) blister pack configurations.

Reviewer Note:

e. DATA TO SUPPORT IVIVC AND/OR PBBM MODELING, IF APPLICABLE.

Not applicable. No IVIVC is claimed for this product; PBBM modeling has not been performed.

The FDA’s Assessment: Not Applicable


No IVIVC or PBBM modeling report was included in the NDA.


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9. LABELINGUSPIHighlights: Adequate

Evaluation:


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Section 2 (if relevant): Adequate

Evaluation: The drug product blisters are designed on Dose reduction. Refer to the How Supplied section of this review.

Section 3 Dosage Forms and Strengths: Adequate

Evaluation:

Section 11 Description: Adequate


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If the following excipients used in the drug product, include warning/declaration in the USPI:

Evaluation: Capsule shell and capsule ink contain iron oxide (E172), an USP/NF, excipient. Applicant calculated the maximum daily exposure of iron. The recommended maximum daily dose of 125 mg. At this dose, the maximum iron exposure would result in the ingestion of a total mg iron per day. Infigratinib capsules meet the < 5 mg elemental iron per day as per the requirements of 21 CFR 73.1200(c), therefore is not listed in this section. Adequate


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Section 16 How Supplied/Storage and Handling: Adequate


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Evaluation:

Manufacturer Information (Name and Address): Provided: Adequate


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Carton/Container Label Adequate

Refer to the Labelling.

Evaluation: Adequate

Item Comments on the Information Provided in NDA

Proprietary name, established name (font size and prominence (21 CFR 201.10(g)(2))

The proprietary and established names are presented correctly. The font size of established name is greater than 50% of the proprietary name.Adequate

Dosage strength (21CFR 201.10(d)(1); 21.CFR 201.100(b)(4))

Since it is a dose pack, total dose/day is listed but strengths (25 and 100 mg) are also correctly expressed. Adequate

Net contents (21 CFR 201.51(a)) The net content is correctly described on each dose packs. Adequate

“Rx only” displayed prominently on the main panel

The statement is prominently displayed.Adequate

NDC number (21 CFR 201.2; 21 CFR 207.35(b)(3)(i))

NDC number is indicated.Adequate

Lot number and expiration date (21 CFR 201.17)

There is a space allocated for this information.Adequate

Storage conditions Storage condition is correctly described.Adequate

Bar code (21CFR 201.25) Barcode is indicated. AdequateName of manufacturer/distributor per 21CFR 201.1.

The name of manufacturer is correctly described. Adequate

And others, if space is available N/A


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Final Risk Assessments

[FDA will complete this section.]To the Review Team: Keep the appropriate Table; delete the rest

SOLID ORALInitial Risk Identification Review Assessment

Attribute/ CQA Factors that can impact the CQA

Risk Ranking

Risk Mitigation Approach

Final Risk Evaluation

Lifecycle Considerations/

CommentsAssay, stability • Formulation

• Container closure• Raw materials• Process parameters• Scale/equipment• Site

Medium Medium Trends of two degradants.

Physical stability (solid state)

• Formulation• Raw materials• Process parameters• Scale/equipment• Site

Low Low N/A

Content Uniformity • Formulation• Container closure• Raw material• Process Parameters• Scale/equipment• Site

Low Low Conforms to USP <905>

No trends observed.

• Formulation• Container closure• Process parameters• Scale/equipment• Site

Low Low Conforms to USP

No trends observed.

Microbial Limits • Formulation• Raw materials• Process parameters• Scale/equipment• Site

Low Low Conforms to USP <61> and <62>.

No trends observed.

Dissolution – BCS Class II & IV

• Formulation• Container Closure• Raw materials• Process parameters• Scale/equipment• Site

Medium Low N/A


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Recommendation Page


Drug Substance: Approval

Primary Reviewer: Soumya Mitra, Ph.D. Date: March 1, 2021Secondary Reviewer: Ali Al-Hakim, Ph.D. Date: March 04, 2021

Drug Product: Approval

Primary Reviewer: Rajiv Agarwal, Ph.D. Date: January 7, 2021Secondary Reviewer: Anamitro Banerjee, Ph.D. Date: January 19, 2021

Process and Facility: Approval

Primary Reviewer: Diane Goll Date: March 10, 2021Secondary Reviewer: Rakhi Shah Date: March 10, 2021

Biopharmaceutics: Approval

Primary Reviewer: Gerlie Gieser, Ph.D. Date: February 19, 2021Secondary Reviewer Banu Zolnik, Ph.D. Date: March 9, 2021

Application Technical Lead: Approval

Xing Wang, Ph.D. Date: March 16, 2021


--------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically. Following this are manifestations of any and allelectronic signatures for this electronic record.--------------------------------------------------------------------------------------------/s/------------------------------------------------------------

XING WANG03/16/2021 03:08:26 PM

SOUMYA MITRA03/16/2021 03:10:51 PM

ALI H AL HAKIM03/16/2021 03:17:21 PM

RAJIV AGARWAL03/16/2021 03:43:08 PM

ANAMITRO BANERJEE03/16/2021 03:48:18 PM

DIANE W GOLL03/16/2021 05:14:47 PM

RAKHI B SHAH03/16/2021 07:21:44 PM

GERLIE GIESER03/17/2021 07:07:16 AM

BANU S ZOLNIK03/17/2021 07:59:44 AM

Signature Page 1 of 1
