Product Quality Review(s) - Food and Drug Administration...This NDA provides for a single 600 mg strength of lefamulin oral tablets, indicated for the treatment of community-acquired

CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

211672Orig1s000 211673Orig1s000

PRODUCT QUALITY REVIEW(S)

QUALITY ASSESSMENT

Recommendation: Approval

NDA 211672

Review # 1

Drug Name/Dosage

Form

Lefamulin/Tablet

Strength 600 mg

Route of

Administration

Oral

Rx/OTC Dispensed Rx

Applicant Nabriva Therapeutics Ireland DAC

US agent, if applicable N/A

SUBMISSION(S)

REVIEWED

DOCUMENT

DATE

DISCIPLINE(S) AFFECTED

eCTD 0031 05/08/2019 Quality

eCTD 0017 03/21/2019 Quality

eCTD 0016 03/19/2019 Quality

eCTD 0015 03/18/2019 Quality

eCTD 0013 03/07/2019 Quality

eCTD 0012 02/27/2019 Quality

eCTD 0007 02/07/2019 Quality

eCTD 0001 12/19/2018 All disciplines

Quality Review Team

DISCIPLINE PRIMARY REVIEWER SECONDARY REVIEWER

Drug Master File/Drug

Substance

Rohit Tiwari Suong Tran

Drug Product George Lunn Balajee Shanmugam

Process Sateesh Sathigari Arwa ElHagrasy

Microbiology Sateesh Sathigari Arwa ElHagrasy

Facility Sateesh Sathigari Arwa ElHagrasy

Biopharmaceutics Gerlie Gieser Elsbeth Chikhale

OPQ-XOPQ-TEM-0001v05 Page 1 of 7 Effective Date: October 15, 2017

Reference ID: 4480095

QUALITY ASSESSMENT

Regulatory Business

Process Manager

Anh-Thy Ly

Application Technical Lead Erika E. Englund

Laboratory (OTR)

ORA Lead Caryn McNab

Environmental

Quality Review Data Sheet

IQA Review Guide Reference

1. RELATED/SUPPORTING DOCUMENTS

A. DMFs:

DMF # Type Holder Item

Referenced Status

Date Review

Completed Comments

Type II Adequate 03/22/2019 Reviewed by Rohit Tiwari

Variable Type III

(if

applicabl

e)

Refer to

DS and

DP

reviews

(b) (4) (b) (4)

B. Other Documents: IND, RLD, or sister applications

DOCUMENT APPLICATION NUMBER DESCRIPTION

NDA 211673 Lefamulin injection

IND 106594

IND 125546

2. CONSULTS

DISCIPLINE STATUS RECOMMENDATION DATE REVIEWER

Biostatistics N/A

Pharmacology/Toxicology Refer to DS and DP

reviews

OPQ-XOPQ-TEM-0001v04 Page 2 of 7 Effective Date: 14 February 2017


QUALITY ASSESSMENT

CDRH N/A

Clinical N/A

Other N/A

Executive Summary


I. Recommendations and Conclusion on Approvability

The NDA, as amended, has provided Adequate CMC information to assure the identity,

strength, purity, and quality of the proposed drug product. All information requests and

review issues have been addressed and there are no pending approvability issues. The

manufacturing and testing facilities for this NDA are deemed acceptable and an overall

“Approve” recommendation was entered into Panorama by the Office of Process and

Facilities (OPF) on May 8, 2019. Therefore, this NDA is recommended for Approval

by the Office of Pharmaceutical Quality (OPQ).

The results from the Method Verification Request are pending. An addendum to the

IQA will be submitted after the method verification report is received.

II. Summary of Quality Assessments

A. Product Overview

This NDA provides for a single 600 mg strength of lefamulin oral tablets, indicated for

the treatment of community-acquired bacterial pneumonia. This product was granted

QIDP, fast track designation, and Priority Review.

The tablets are blue, oval, coated immediate release tablets with “LEF600” printed in

black on one side. The maximum recommended daily dose of lefamulin is 1200 mg.

This NDA cross-references NDA 211673, which describes lefamulin for injection. The

development of lefamulin is described in IND 106594 (intravenous formulation) and

IND 125546 (oral formulation).

No dosage adjustment is described in the PI. The PI describes that the tablets should be

swallowed whole (not crushed or divided). Tablets should be stored at 20°C to 25°C

(68°F to 77°F);



QUALITY ASSESSMENT

0 Total Number of Comparability Protocols (ANDA only)

Proposed Indication(s) including

Intended Patient Population

Treatment of adult patients with community-acquired

bacterial pneumonia (CABP) caused by susceptible

microorganisms

Duration of Treatment 7 days

Maximum Daily Dose 150 mg every 12 h by IV infusion (5-7 days) 150 mg every 12 h by IV infusion, then 600 mg

orally every 12 h (5-7 days)

600 mg orally every 12 h (5 days) Alternative Methods of

Administration

Oral or by intravenous infusion

B. Quality Assessment Overview

Drug Substance:

The drug substance, lefamulin acetate, is a white to off-white solid, and a single

stereoisomer. The applicant provided characterization data that is in agreement with the

proposed structure, and the drug substance specification includes polymorph testing.

The manufacturing process produced only the desired,

polymorph (b) (4)

(b) (4)

Lefamulin is semi-synthetically derived from pleuromutilin, a natural fermentation

product of known absolute stereochemistry. The synthetic starting material is

DMF

was referenced for the supporting CMC information of and was found

adequate. The applicant provided the manufacturing process description for

with detailed description for the critical process parameters and critical in process

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

controls. The manufacturing process does not employ any toxic elements or Class 1

solvents.

The specification includes impurity with limits above the and (b) (4) (b) (4)

ICHQ3A qualification thresholds. The control of the drug substance impurities was

found acceptable from a CMC perspective. Refer to the non-clinical review concerning

the safety assessment of the impurities. The applicant provided the results of elemental

impurities as per USP in the registration batches and the levels of class 1 toxic

metals were found to be below % of the ICH proposed limits. Therefore, the (b) (4)



QUALITY ASSESSMENT

applicant proposed to exclude this test from the drug substance specification and it is

acceptable. The specifications, analytical methods and their validation for the drug

substance are reasonable to ensure and meet the standards in the specifications

The proposed drug substance retest date of months when stored under the long-term

conditions is acceptable.

(b) (4)

(b) (4)

This NDA is recommended for approval from a Drug Substance perspective. For

further details, refer to the drug substance review by Rohit Tiwari.

Drug Product:

The drug product consists of a blue oval immediate release film-coated tablet with

LEF600 printed in black on one side. The inactive ingredients are mannitol, povidone

K30, microcrystalline cellulose, croscarmellose sodium, talc, colloidal silicon dioxide,

magnesium stearate, polyvinyl alcohol, (b) (4)

partially hydrolyzed, titanium dioxide, polyethylene glycol, talc, and FD&C Blue No 2

Aluminum Lake. shellac glaze, ferrosoferric oxide,

The excipients are compendial or comprised of compendial materials.

(b) (4)

(b) (4)

The specification contains tests for appearance, identity, assay, impurities, weight

uniformity, dissolution, disintegration, water, and microbial limits and is reasonable.

In general, the specification conforms to USP and ICH recommendations and generally

reflect manufacturing capability. The PharmTox reviewer agrees that the impurity

is toxicologically qualified at %. The analytical methods are described in

(b) (4)

(b) (4)

reasonable detail and have been validated. Methods verification in an FDA laboratory

is ongoing. Satisfactory batch analyses are provided for three batches of blue tablets

and 3 batches of the very similar yellow tablets.

The container-closure system consists of blisters and white opaque HDPE bottles

with CRCs and seals. Photostability testing has been carried out and there (b) (4)

(b) (4)

was no appreciable change to the exposed tablets.

Satisfactory stability data are supplied for 8 batches stored at 25°C/60% RH for 12-36

months, 3 batches stored at 30°C/75% RH for 12 months, and 8 batches stored for 6

months at 40°C/75% RH. In particular 2 batches were stored at 25°C/60% RH for 36

months and 3 batches were stored under these conditions for 24 months. It is

noteworthy that different film coats were used for different batches, but this should not

affect the stability data. No significant batch to batch variations were noted. At

25°C/60% RH and 30°C/75% RH there are no out of specification results and no

obvious trends. The largest impurity observed is %. The variations in the impurity (b) (4)

levels seem to be mostly due to variations in the initial drug substance batch. The

content increases more with the blisters and total impurities may be

slightly higher at 40°C/75% RH but the differences are slight. The dissolution values

(b) (4) (b) (4)



QUALITY ASSESSMENT

remain within a reasonable range. The applicant claims an expiration dating period of

36 months for tablets stored at 25°C (USP controlled room temperature) in HDPE

bottles and blisters. Based on the data submitted this expiration dating period is (b) (4)

reasonable.

This NDA is recommended for approval from a Drug Product perspective. For

additional details, refer to the review by George Lunn.

Process and Facilities:

The manufacturing process for the proposed NDA drug product includes the following

steps:

The proposed maximum

targeted commercial batch size tablets) is similar to registration batch size.

(b) (4)

(b) (4)

There are 7 facilities listed in this NDA, and all facilities were recommended for

approval in this NDA. One post-approval inspection was recommended for

(FEI # ).

The applicant included deviation report # DRF in the NDA which described

extraneous matter in the API. The extraneous matter was identified as

that is used in the manufacturing. Upon review, the OPF reviewer felt

(b) (4)

(b) (4)

(b) (4)

(b) (4)

additional information was needed to assess this incident impact on the drug quality of

the registration drug product batches and future commercial manufacturing. Additional

information was requested directly from drug substance manufacturer. The response

and its evaluation are documented under CMS WA # 268392. The drug substance

manufacturer corrective and preventive actions for this incident were found to be

adequate. OPF recommends approval of this facility for its commercial manufacturing

responsibilities. However, due to this and other noted non-conformance incidents

(Refer CMS WA # 268392) during review of the information from the drug substance

facility, this facility is recommended for a post – approval inspection.

This NDA is recommended for approval from a Process and Facilities perspective. For

additional details, refer to the review by Sateesh Sathigari.

Biopharmaceutics:

The proposed dissolution method and acceptance criteria (Q = % at 60 min) are

found acceptable for quality control of the proposed drug product. The proposed to-be

(b) (4)

marketed tablet is the same as the Phase 3 clinical trial material in terms of formulation

composition, drug product manufacturing process and site, and drug substance

manufacturer. The only difference is in appearance (blue coating with black imprint vs.

yellow coating and unmarked). The registration batches have a slightly higher rate of

dissolution than the Phase 3 clinical trial lots, but this was not considered a safety

concern for these immediate release tablets.



QUALITY ASSESSMENT

A formal BCS Designation Request was not submitted, but the applicant considers this

drug substance to be BCS Class III (high solubility/low permeability). A biowaiver is

not requested nor required.

This NDA is recommended for approval from a Biopharmaceutics perspective. For

further details, refer to the review by Gerlie Gieser.

Environmental Assessment:

The applicant has submitted a claim of categorical exclusion. The categorical exclusion

cited at 21 CFR 25.31(b) is appropriate for the estimated amount of drug to be

produced for direct use. A statement of no extraordinary circumstances has been

submitted. The claim of categorical exclusion is acceptable.

For additional details, refer to the Drug Product review by George Lunn.

Method Verification:

The method verification report is pending. An addendum to this IQA will be submitted

after the verification has been completed.

C. Special Product Quality Labeling Recommendations (NDA only)

The labeling recommendations were communicated to the OND PM.

D. Final Risk Assessment (see Attachment)



QUALITY ASSESSMENT


NDA 211672

Review # 2

Drug Name/Dosage

Form

Lefamulin/Tablet

Strength 600 mg

Route of

Administration

Oral

Rx/OTC Dispensed Rx



SUBMISSION(S)

REVIEWED

DOCUMENT

DATE


eCTD 0036 5/30/2019 Quality

eCTD 0039 06/05/2019 Quality


1. RELATED/SUPPORTING DOCUMENTS and QUALITY REVIEW TEAM

Refer to CMC Review #1

Executive Summary











QUALITY ASSESSMENT


A. Product Overview

Refer to CMC Review #1 for a complete discussion.

In CMC Review #1, the OPF review discussed extraneous matter observed in the API.

Following discussion with the clinical and pharmacology/toxicology teams, the

following IR was sent on May 24, 2019 to confirm that batch 38337 would not be used

for any human use. The applicant responded on 5/30/2019 that this batch would not be

used for human use. They also wrote that the drug substance validation batches are free

from contamination. These responses are acceptable.

QUESTION 1: We have reviewed your response to process comment # 7 regarding the extraneous

matter observation that was reported during execution of registration batches

W038336 and W038338, and have following comments:

a. We do not agree with your proposal and justification to release batch # W038337 for clinical or any human use. Even though the extraneous matter is observed in

one lot of API (# 17NB26.HE00001) that has been used in the manufacturing of

two registration batches (W038336 and W038338), the agency considers that

batch # W038337, that used a different lot of API, to be potentially contaminated

with the extraneous matter

in between the batches. The toxicological

(b) (4)

information provided does not adequately assess or define the potential adverse

effects associated with , nor does it describe a no (b) (4)

adverse effect level (NOAEL).

b. Process Performance Qualification (PPQ) batches should not be manufactured with any of the potentially contaminated API lots. According to 21 U.S.C.351

(a)(2)(B)), a drug shall be deemed to be adulterated if the methods used in, or the

facilities or controls used for, it manufacture, processing, packing, or holding do

not conform to or are not operated or administered in conformity with current

good manufacturing practice to assure that such drug meets the requirements of

this Act as to safety and has the identity and strength, and meets the quality and

purity characteristics, which it purports or is represented to possess. Please

acknowledge this in your response.


Drug Substance:




QUALITY ASSESSMENT

Drug Product:

At the time of CMC Review #1, the methods verification in an FDA laboratory was

ongoing. The IR below was sent on 5/29/2019 regarding the findings from the method

verification:

We are reviewing the Chemistry, Manufacturing, and Control section(s) of your

submission and have the following comments and information requests. We request

a prompt written response by June 5, 2019 in order to continue our evaluation of

your NDA. We have received from our laboratory a Method Verification report for

the HPLC Method for Identity, Assay and Impurities for NDA 211672. Some

excerpts are provided below. After the initial report was received we asked our

laboratory to rerun the analysis at nm. They reported that the sample solution

still had the rising baseline issue. The peak area response for the main peak sample

was less at nm compared to nm by ~ three fold. The unknown at RRT

that was out of specification at nm meets specification at nm. (At nm the

area of the

unknown peak is times lower compared to the nm run.)

(b) (4)

(b) (4) (b) (4) (b) (4)

(b) (4)(b) (4)(b) (4)

(b) (4)

(b) (4)

Within 1 week please comment on the observations made by our laboratory and

specifically address the following points.

a) Provide a rationale for running the analysis of the tablets at nm in contrast to

the analyses for the drug substance and injection which are run at nm.

b) Provide an evaluation of the non-linearity of the method.

(b) (4)

(b) (4)

c) Provide a sample chromatogram of the placebo. The laboratory identified an

unknown peak at RRT . Clarify if this unknown peak is attributed to the placebo, (b) (4)

or provide the identity of this unknown peak. In addition, clarify if this unknown

peak was identified in other batches of the drug product.

The applicant responded on 6/5/2019. They provided a placebo chromatogram to

demonstrate that the unknown peak at RRT was not a degradant, explained that

the assay is run a nm to minimize interference from the excipient povidone, and

(b) (4)

(b) (4)

provided justification for the non-linear observation. This response is acceptable.


additional details, refer to the reviews by George Lunn.


The applicant responded to Question 1 on 05/29/2019 and stated that the registration

batch # W038337 will not be used in humans. PPQ batches are manufactured using drug

substance free of any contamination. The response was evaluated by OPF and found

satisfactory. The NDA is approval from manufacturing perspective.



QUALITY ASSESSMENT


Biopharmaceutics:





The method verification report was pending at the time of CMC Review #1. The final

method verification report included a suggestion for a linear regression fit, and includes

observations of an unknown peak at RRT and a rising baseline. An IR was sent to

the applicant with the findings from this verification report, and the response was

evaluated by the drug product reviewer.

(b) (4)







Erika Digitally signed by Erika Englund Date: 7/12/2019 05:22:06PMEnglund GUID: 51389ea30003450414230afb8c3e8114


QUALITY ASSESSMENT


NDA 211672

Review # 1

Drug Name/Dosage

Form

Lefamulin/Tablet

Strength 600 mg

Route of

Administration

Oral

Rx/OTC Dispensed Rx



SUBMISSION(S)

REVIEWED

DOCUMENT

DATE


eCTD 0031 05/08/2019 Quality

eCTD 0017 03/21/2019 Quality

eCTD 0016 03/19/2019 Quality

eCTD 0015 03/18/2019 Quality

eCTD 0013 03/07/2019 Quality

eCTD 0012 02/27/2019 Quality

eCTD 0007 02/07/2019 Quality

eCTD 0001 12/19/2018 All disciplines

Quality Review Team

DISCIPLINE PRIMARY REVIEWER SECONDARY REVIEWER

Drug Master File/Drug

Substance

Rohit Tiwari Suong Tran

Drug Product George Lunn Balajee Shanmugam

Process Sateesh Sathigari Arwa ElHagrasy

Microbiology Sateesh Sathigari Arwa ElHagrasy

Facility Sateesh Sathigari Arwa ElHagrasy

Biopharmaceutics Gerlie Gieser Elsbeth Chikhale



QUALITY ASSESSMENT

Regulatory Business

Process Manager

Anh-Thy Ly

Application Technical Lead Erika E. Englund

Laboratory (OTR)

ORA Lead Caryn McNab

Environmental



1. RELATED/SUPPORTING DOCUMENTS

A. DMFs:

DMF # Type Holder Item

Referenced Status

Date Review

Completed Comments

Type II Adequate 03/22/2019 Reviewed by Rohit Tiwari

Variable Type III

(if

applicabl

e)

Refer to

DS and

DP

reviews

(b) (4) (b) (4)

B. Other Documents: IND, RLD, or sister applications

DOCUMENT APPLICATION NUMBER DESCRIPTION

NDA 211673 Lefamulin injection

IND 106594

IND 125546

2. CONSULTS

DISCIPLINE STATUS RECOMMENDATION DATE REVIEWER

Biostatistics N/A

Pharmacology/Toxicology Refer to DS and DP

reviews



QUALITY ASSESSMENT

CDRH N/A

Clinical N/A

Other N/A

Executive Summary










The results from the Method Verification Request are pending. An addendum to the

IQA will be submitted after the method verification report is received.


A. Product Overview

This NDA provides for a single 600 mg strength of lefamulin oral tablets, indicated for

the treatment of community-acquired bacterial pneumonia. This product was granted

QIDP, fast track designation, and Priority Review.

The tablets are blue, oval, coated immediate release tablets with “LEF600” printed in

black on one side. The maximum recommended daily dose of lefamulin is 1200 mg.

This NDA cross-references NDA 211673, which describes lefamulin for injection. The

development of lefamulin is described in IND 106594 (intravenous formulation) and

IND 125546 (oral formulation).

No dosage adjustment is described in the PI. The PI describes that the tablets should be

swallowed whole (not crushed or divided). Tablets should be stored at 20°C to 25°C

(68°F to 77°F);



QUALITY ASSESSMENT

0 Total Number of Comparability Protocols (ANDA only)

Proposed Indication(s) including

Intended Patient Population

Treatment of adult patients with community-acquired

bacterial pneumonia (CABP) caused by susceptible

microorganisms

Duration of Treatment 7 days

Maximum Daily Dose 150 mg every 12 h by IV infusion (5-7 days) 150 mg every 12 h by IV infusion, then 600 mg

orally every 12 h (5-7 days)

600 mg orally every 12 h (5 days) Alternative Methods of

Administration

Oral or by intravenous infusion


Drug Substance:

The drug substance, lefamulin acetate, is a white to off-white solid, and a single

stereoisomer. The applicant provided characterization data that is in agreement with the

proposed structure, and the drug substance specification includes polymorph testing.

The manufacturing process produced only the desired, ,

polymorph (b) (4)

(b) (4)

Lefamulin is semi-synthetically derived from pleuromutilin, a natural fermentation

product of known absolute stereochemistry. The synthetic starting material is

DMF

was referenced for the supporting CMC information of , and was found

adequate. The applicant provided the manufacturing process description for

with detailed description for the critical process parameters and critical in process

controls. The manufacturing process

The specification includes impurity and with limits above the

(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)

ICHQ3A qualification thresholds. The control of the drug substance impurities was

found acceptable from a CMC perspective. Refer to the non-clinical review concerning

the safety assessment of the impurities. The applicant provided the results of elemental

impurities as per USP in the registration batches and the levels of class 1 toxic

metals were found to be below % of the ICH proposed limits. Therefore, the (b) (4)



QUALITY ASSESSMENT

applicant proposed to exclude this test from the drug substance specification and it is

acceptable. The specifications, analytical methods and their validation for the drug

substance are reasonable to ensure and meet the standards in the specifications

The proposed drug substance retest date of months when stored under the long-term

conditions is acceptable.

(b) (4)

(b) (4)

This NDA is recommended for approval from a Drug Substance perspective. For

further details, refer to the drug substance review by Rohit Tiwari.

Drug Product:

The drug product consists of a blue oval immediate release film-coated tablet with

LEF600 printed in black on one side. The inactive ingredients are mannitol, povidone

K30, microcrystalline cellulose, croscarmellose sodium, talc, colloidal silicon dioxide,

magnesium stearate, polyvinyl alcohol, (b) (4)

partially hydrolyzed, titanium dioxide, polyethylene glycol, talc, and FD&C Blue No 2

Aluminum Lake. shellac glaze, ferrosoferric oxide,

The excipients are compendial or comprised of compendial materials.

(b) (4)

(b) (4)

The specification contains tests for appearance, identity, assay, impurities, weight

uniformity, dissolution, disintegration, water, and microbial limits and is reasonable.

In general, the specification conforms to USP and ICH recommendations and generally

reflect manufacturing capability. The PharmTox reviewer agrees that the impurity

is toxicologically qualified at %. The analytical methods are described in

(b) (4)

(b) (4)

reasonable detail and have been validated. Methods verification in an FDA laboratory

is ongoing. Satisfactory batch analyses are provided for three batches of blue tablets

and 3 batches of the very similar yellow tablets.

The container-closure system consists of blisters and white opaque HDPE bottles

with CRCs and seals. Photostability testing has been carried out and there (b) (4)

(b) (4)

was no appreciable change to the exposed tablets.

Satisfactory stability data are supplied for 8 batches stored at 25°C/60% RH for 12-36

months, 3 batches stored at 30°C/75% RH for 12 months, and 8 batches stored for 6

months at 40°C/75% RH. In particular 2 batches were stored at 25°C/60% RH for 36

months and 3 batches were stored under these conditions for 24 months. It is

noteworthy that different film coats were used for different batches, but this should not

affect the stability data. No significant batch to batch variations were noted. At

25°C/60% RH and 30°C/75% RH there are no out of specification results and no

obvious trends. The largest impurity observed is %. The variations in the impurity (b) (4)

levels seem to be mostly due to variations in the initial drug substance batch. The

content increases more with the blisters and total impurities may be

slightly higher at 40°C/75% RH but the differences are slight. The dissolution values

(b) (4) (b) (4)



QUALITY ASSESSMENT

remain within a reasonable range. The applicant claims an expiration dating period of

36 months for tablets stored at 25°C (USP controlled room temperature) in HDPE

bottles and blisters. Based on the data submitted this expiration dating period is (b) (4)

reasonable.


additional details, refer to the review by George Lunn.


The manufacturing process for the proposed NDA drug product includes the following

steps:

The proposed maximum

targeted commercial batch size ( tablets) is similar to registration batch size.

(b) (4)

(b) (4)

There are 7 facilities listed in this NDA, and all facilities were recommended for

approval in this NDA. One post-approval inspection was recommended for

(FEI # ).

The applicant included deviation report # DRF in the NDA which described

extraneous matter in the API. The extraneous matter was identified as

that is used in the manufacturing. Upon review, the OPF reviewer felt

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

additional information was needed to assess this incident impact on the drug quality of

the registration drug product batches and future commercial manufacturing. Additional

information was requested directly from drug substance manufacturer. The response

and its evaluation are documented under CMS WA # 268392. The drug substance

manufacturer corrective and preventive actions for this incident were found to be

adequate. OPF recommends approval of this facility for its commercial manufacturing

responsibilities. However, due to this and other noted non-conformance incidents

(Refer CMS WA # 268392) during review of the information from the drug substance

facility, this facility is recommended for a post – approval inspection.

This NDA is recommended for approval from a Process and Facilities perspective. For

additional details, refer to the review by Sateesh Sathigari.

Biopharmaceutics:

The proposed dissolution method and acceptance criteria (Q = % at 60 min) are

found acceptable for quality control of the proposed drug product. The proposed to-be

(b) (4)

marketed tablet is the same as the Phase 3 clinical trial material in terms of formulation

composition, drug product manufacturing process and site, and drug substance

manufacturer. The only difference is in appearance (blue coating with black imprint vs.

yellow coating and unmarked). The registration batches have a slightly higher rate of

dissolution than the Phase 3 clinical trial lots, but this was not considered a safety

concern for these immediate release tablets.



QUALITY ASSESSMENT

A formal BCS Designation Request was not submitted, but the applicant considers this

drug substance to be BCS Class III (high solubility/low permeability). A biowaiver is

not requested nor required.

This NDA is recommended for approval from a Biopharmaceutics perspective. For

further details, refer to the review by Gerlie Gieser.


The applicant has submitted a claim of categorical exclusion. The categorical exclusion

cited at 21 CFR 25.31(b) is appropriate for the estimated amount of drug to be

produced for direct use. A statement of no extraordinary circumstances has been

submitted. The claim of categorical exclusion is acceptable.

For additional details, refer to the Drug Product review by George Lunn.


The method verification report is pending. An addendum to this IQA will be submitted

after the verification has been completed.


The labeling recommendations were communicated to the OND PM.


66 Page(s) have been Withheld in Full as B4 (CCI/TS) immediately following this page



QUALITY ASSESSMENT

BIOPHARMACEUTICS

Product Background:

NDA: 211672

Drug Product Name / Strength: Lefamulin Tablet / 600 mg (base)

Route of Administration: Oral

Proposed Dosage (for the treatment of community-acquired bacterial pneumonia,

following treatment with Lefamulin for Injection 150 mg every 12 hours by IV

infusion): 600 mg orally every 12 hours for 5 days or at the

discretion of the physician. Swallow tablets whole (do not crush or divide).

Applicant Name: Nabriva

Primary Biopharmaceutics Reviewer: Gerlie Gieser, Ph.D.

Secondary Biopharmaceutics Reviewer: Elsbeth Chikhale, Ph.D.

Review Recommendation: APPROVAL

Review Summary:

The proposed dissolution method and acceptance criterion (as tabulated below) are approved for the routine QC of the proposed drug product at batch release and during

stability testing.

USP

Apparatus Speed Medium Volume Acceptance criterion

2 (paddle) 50 rpm 0.1N HCl,

37 ± 0.5°C 1000 mL Q = % (Q) at 60 min

The Phase 3 clinical trial lots and the final commercial image tablets have similar in vitro dissolution profiles, and thus are adequately bridged.

Biowaiver was not requested nor is required.

Over-encapsulation of Avelox and Zyvox tablets (to accomplish blinding of the Phase 3 clinical trials) did not impact that in vitro dissolution profiles of the tablets.

(b) (4)

(b) (4)



QUALITY ASSESSMENT

List of Submissions reviewed:

SDN-1, 12/19/2018 (Original NDA) SDN-7, 2/7/2019 (Response to Quality Information Request)

Concise Description of Outstanding Issues Remaining:

None

BCS Designation

There is no formal BCS Designation Request for the proposed oral tablet although the

Applicant considers lefamulin acetate as a BCS Class III (high solubility/low

permeability) drug substance.

Reviewer’s Assessment:

Solubility: High. The solubility of lefamulin acetate is ≥ 100 mg/mL in 0.1 N HCl and

300 mM phosphate buffers at pH 6.8 and pH 7.4, and >300 mg/mL in water and 0.9%

sodium chloride solution. The Applicant indicated that the solubility of the drug

substance is high (>100 mg/mL) across the physiologic pH range, regardless of API

polymorphic form see Table 6 of SDN-7. Per the proposed labeling of

lefamulin tablet, the maximum recommended single dose is 600 mg (as lefamulin

base).

Permeability: Low. The absolute bioavailability of the oral tablet under fasted

conditions was ~25%; under fed conditions, 21% (see page 9 of the proposed labeling).

Dissolution: Not Rapid or Very Rapid. Per the Applicant, the dissolution of the tablets

Using USP Apparatus 2 (paddle) rotating at 50 rpm,

and 1000 mL of various pH buffer media, less than % of the label claim of lefamulin

dissolves within minutes (see Figure 3 below).

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Dissolution Method and Acceptance Criterion


Dissolution Method – ADEQUATE

Justification for Chosen Method Parameters

Acidic medium (0.1N HCl) was chosen to simulate physiologic conditions of dissolution in the

stomach, in addition to achieving sink conditions during routine QC dissolution testing. The

relatively low paddle speed (50 rpm) was selected to maximize the dissolution method’s

discriminating power.



QUALITY ASSESSMENT

Discriminating Power

Overall, the provided data demonstrated that the proposed QC dissolution method has adequate

discriminating power for changes in the critical quality attributes of the drug product.

Specifically, the proposed QC dissolution method was demonstrated to be capable of detecting

intentional changes in the levels of the excipient, i.e., the (Povidone K90),

(croscarmellose sodium), and (magnesium stearate); see Figure 1. The comparative in

(b) (4) (b) (4)

(b) (4)

vitro dissolution profile data in Figure 1 provide direct evidence that the proposed dissolution

method is capable of rejecting drug products with quality attributes that could result in

unacceptably low dissolution rates.

Fig hes

(b) (4)

Source: Figure 11 of the Pharmaceutical Development Report (PDR).

See Table 12 of the PDR for the compositions of the variant drug product batches.

Additionally, the proposed QC dissolution method was able to detect the slightly faster

dissolution rate of the registration lots (see Figure 3 below). The Applicant pointed out that

compared to the Phase 3 clinical lots, the manufacture of the registration lots used a slightly

which resulted in the slight reduction in the registration lots’

and consequently, the requirement to (b) (4)

(b) (4)

(b) (4)

[Notes: API particle size distribution (PSD) differences within the studied ranges (d10: μm,

d50: μm, d90: μm) were not shown to impact dissolution profile (Table 10/Figure

9 of 3.2.P.2 PDR), likely because the drug substance is highly soluble (per BCS criteria). Both

API were reported to be highly soluble. Disintegration (NMT min),

and (NMT %) are part of the finished product QC specifications.] (b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

Stability-Indicating Potential

The proposed QC dissolution method has stability indicating potential as shown by the

significant reduction in the dissolution (and disintegration, with a slight increase in )

of the tablets stored in under accelerated conditions (40°C/75%RH), but not (b) (4)

(b) (4)



QUALITY ASSESSMENT

those stored under 25°C/60%RH conditions. [Based on the study findings, HDPE bottles and

blisters were chosen as the commercial packaging configurations of the proposed drug (b) (4)

product; see Figures 13 to 15 of the PDR.]

[Additionally, based on the (b) (4) and dissolution profiles of Registration Batch

W038336 during open-dish stress stability testing, this Reviewer considers reasonable (but defers

to the Drug Product Reviewer the final determination regarding the acceptability of) the proposed

limit of NMT %; see Table 5 of the 2/7/2019 Response to FDA Quality Comment

#2 dated 1/25/2019 (SDN-7), and Figure 12 of the PDR.]

(b) (4) (b) (4)

Analytical Method Validation

The drug in the dissolution sample is quantified using reversed-phase isocratic HPLC method

with UV detection at 244 nm. The analytical method was validated for specificity, linearity,

accuracy, precision, robustness (in terms of HPLC and dissolution parameters including paddle

speed (± 5 rpm), medium temperature (± 5º C). The standard and the samples solutions were

reported to be stable for up to 96 hours at room temperature and refrigerated conditions. Per the

Drug Product Reviewer (Dr. George Lunn), the analytical methods validation including that for

dissolution testing is adequate.

Dissolution Acceptance Criterion – ACCEPTABLE

Per the Applicant, the proposed dissolution acceptance criterion (Q = % at 60 min) was based

on the mean dissolution profile data (default Stage 2 testing) of the Phase 3 clinical trial lots at

batch release and during stability testing.

Based on the dissolution profile data of the Phase 3 clinical trial lots at batch release and during

24 to 36 months of long-term (25 °C/60% RH) storage, this Reviewer considers reasonable the

proposed QC dissolution acceptance criterion (Q = % at 60 min). Additionally, based on

studies involving drug product batches with quantitative alterations in the level of excipients (as

depicted in Figure 11), ‘Q = % at 60 min’ is sufficient to reject tablet batches with substantially

low levels of the disintegrant and high levels of the lubricant.

(b) (4)

(b) (4)

(b) (4)

REVIEWER NOTE: Recently, FDA had determined that it was not necessary to establish

discriminating power for drug products containing highly soluble drug substances, and that the

standard dissolution method(s) as prescribed in the 2018 FDA Guidance on Dissolution Testing

of Immediate Release Drug Products Containing High Solubility Drug Substances can be used.

Since the Applicant’s proposed dissolution method possess discriminating power and stability

indicating potential, and it (along with the appropriate acceptance criterion) does not preclude the

pivotal Phase 3 clinical trial lots from achieving complete dissolution/drug release, this Reviewer

believes that it is not necessary to recommend optimization (e.g., of the dissolution medium

volume) of the proposed QC dissolution method. Additionally, this Reviewer believes that it is

justified to accept the proposed specification time point of 60 min (instead of the Guidance

recommended specification time point of min to achieve a Q of %) for the QC dissolution

acceptance criterion because it represents the start of the dissolution plateau, and is associated

with lower data variability than the earlier dissolution sampling time points, as evidenced by the

(b) (4)

(b) (4)



QUALITY ASSESSMENT

dissolution profile data of the Phase 3 clinical trial lots at batch release and during long-term

storage.

Dissolution on Stability

As shown in Figure 2, there were no apparent trends in the dissolution profiles of the two Phase 3

clinical trial lots during long-term storage, regardless of the primary packaging configuration

blister or HDPE bottles).

The Applicant reported that all stability batches conformed to the proposed dissolution

acceptance criterion, i.e., including the Phase 3 clinical trial lots and the three registration lots

under long-term storage for up to 36 months and up to 12 months, respectively.

Figure 2. Dissolution Profiles of the Pivotal Phase 3 Clinical Trial Lots During

24 months to 36 months of Long-Term Storage

(b) (4)

(b) (4)

Bridging of Formulations

Reviewer’s Assessment: ADEQUATE

The final proposed to-be-marketed tablet is the same as the Phase 3 clinical trial tablet in terms of

formulation composition, manufacturing process and drug product manufacturer as (b) (4)



QUALITY ASSESSMENT

well as the API manufacturer , but not in terms of appearance (blue coating with black

imprint vs. yellow coating/unmarked). The registration and the clinical batch sizes are considered

similar ( kg versus kg, respectively).

Figure 3 shows that the in vitro dissolution profiles of the Phase 3 clinical trial tablets and the final

commercial image tablets (i.e., as represented by the validation and registration batches) in the

proposed QC dissolution medium and in various pH media are comparable, with calculated profile

similarity (f2) values >50.

That the registration stability lots have a slightly faster dissolution rate than the Phase 3 clinical trial

lots is not expected to pose a safety concern for the following reasons: (1) the drug substance

exhibits high solubility in media with pH across the physiologic range, (2) the drug product is an

immediate release oral tablet, and (3) a similar (Phase 1) immediate release lefamulin tablet

formulation with a faster dissolution rate was shown to be bioequivalent (in terms of plasma Cmax

and AUC) to the Phase 3 tablet; see Figure 1 of 2.7.1 Summary of Biopharmaceutics.

Figure 3. Comparative Dissolution Profiles of Pivotal Clinical Trial Lots and Registration Lots

in Various pH Media

Note that PK data for the earlier clinical (capsule and tablet) formulations are available should in

vivo BE bridging to the final tablet formulation be needed.

REVIEWER NOTE:

Regarding the active comparator tablets used in the double-blinded pivotal Phase 3 clinical trials:

The comparative in vitro dissolution profile data provided by the Applicant indicate that the over-

encapsulation of the active comparator (Avelox® and Zyvox®) tablets did not significantly impact

(b) (4)

(b) (4)(b) (4)



QUALITY ASSESSMENT

the moxifloxacin or linezolid dissolution profiles as compared to the unmodified/unencapsulated

tablets. For details, see Figures 1 and 2 and additional information provided in the Applicant’s

2/7/19 Response to the FDA Quality Information Request dated 1/25/2019; SDN-7.

Biowaiver Request

Reviewer’s Assessment: NOT NEEDED

A biowaiver request was not submitted nor required. The final formulation of the

lefamulin 600 mg oral tablet was evaluated in the Phase 3 clinical efficacy and safety

studies (3101 and 3201), and for clinical PK in Studies 1107 (relative BA; food-effect),

1108 (rifampin DDI), 1109 (digoxin DDI), 1110 and 1111 (midazolam DDI).

List of Deficiencies:

None



Gerlie Digitally signed by Gerlie Gieser Date: 4/03/2019 11:56:23AMGieser GUID: 507592ba00003d190b2ea34fe8fb8ccb

Elsbeth Digitally signed by Elsbeth Chikhale Date: 4/03/2019 05:06:52PMChikhale GUID: 50743ccc000031928b54eba1769a5df9


NDA 211672 Lefamulin Tablets

Container and Carton Labeling

Note: These recommendations (except for the child-resistant wording) were combined with the DMEPA recommendations and sent to the applicant on 5/2/19. The child resistant wording was sent on 5/15/19.

Recommendations

Bottle label

Change TRADENAME (b) (4) tablets to TRADENAME (lefamulin) tablets

Delete “ (b) (4)” and add the following to the right hand side of the label

“Each tablet contains 671 mg lefamulin acetate equivalent to 600 mg lefamulin”. This addition

could be omitted for reasons of space.

Blister Package ( (b) (4)

Change TRADENAME (b) (4) tablets to TRADENAME (lefamulin) tablets

Delete “ (b) (4)” and add the following to the top left panel “Each tablet

contains 671 mg lefamulin acetate equivalent to 600 mg lefamulin”.

Names of all the inactive ingredients (as listed on the Package Insert) should be added to the top

left panel.

This package is not child resistant (Amendment of 5/8/19). This package is not mentioned in the

PI because it is not for sale. Having the blister pack be non-child resistant appears to be

acceptable but it should be marked “This Package for Households Without Young Children” in

compliance with 16 CFR 1700.5 (a) (1) but it could be “Package Not Child-Resistant” if the

package is too small (16 CFR 1700.5 (b)). 21 CFR 201.10 (i) which allows for omitting a

warning if the package is too small does not seem applicable. Recommend that we send the

following to the applicant: “Please add “Package Not Child-Resistant” to the blister presentation

in accord with 16 CFR 1700. This could go below the statement “KEEP OUT OF REACH OF

CHILDREN”.”

Review Notes

1) Immediate Container Label


The bottle label is as follows.

(b) (4)

The text of the bottle label is as follows.

NDC 72000-110-30 Rx only TRADENAME tablets (b) (4)

600 mg

30 TABLETS

(b) (4)

Bar Code: GTIN 12345678901234

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight (USP), child-resistant containers. DOSAGE AND ADMINISTRATION. See accompanying full prescribing information. KEEP OUT OF REACH OF CHILDREN. Manufactured for Nabriva Therapeutics US, Inc. King of Prussia, PA 19406 © Nabriva Revised

(b) (4)

(b) (4)

Nabriva Therapeutics [Logo]

LOT EXP SN


(b) (4)

(b) (4)

(b) (4)

Item Information Provided in NDA Conclusions

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

TRADENAME tablets

Change to: TRADENAME (lefamulin) tablets

Strength (21CFR 201.10(d)(1); 21.CFR 201.100(b)(4)) and salt equivalency statement (space permitting)

600 mg Change to: 600 mg Add to right hand side of label: Each tablet contains 671 mg lefamulin acetate equivalent to 600 mg lefamulin [may be omitted for space reasons)

Route of administration 21.CFR 201.100(b)(3))

None Not required because it is oral

Net contents* (21 CFR 201.51(a))

30 tablets Adequate

Name of all inactive ingredients (; Quantitative ingredient information is required for injectables) 21CFR 201.100(b)(5)**

Not present Not required because this is an oral product

Lot number per 21 CFR 201.18

Present Adequate

Expiration date per 21 CFR 201.17

Present Adequate

͞·ϳ ΪΣΜϴ͟ νχ̯χ͋͋Σχ ζ͋ι 21 CFR 201.100(b)(1)

Present Adequate

Storage (not required)

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Adequate

NDC number (per 21 CFR 201.2) (requested, but not required for all labels or labeling), also see 21 CFR 207.35(b)(3)

NDC 72000-110-30 Adequate

Bar Code per 21 CFR 201.25(c)(2)***

Present Adequate

Name of manufacturer/distributor (21 CFR 201.1)

Manufactured for Nabriva Therapeutics US, Inc. King of Prussia, PA 19406 © Nabriva

Adequate


Others Dispense in tight (USP), child-resistant containers.

Acceptable

DOSAGE AND ADMINISTRATION. See accompanying full prescribing information.

KEEP OUT OF REACH OF CHILDREN.

*21 CFR 201.51(h) A drug shall be exempt from compliance with the net quantity declaration required ̼ϴ χ·Ίν ν͋̽χΊΪΣ Ί͕ Ίχ Ίν ̯Σ ΪΊΣχ͋Σχ Μ̯̼͋Μ͇͋ ··ν̯ζΜ͋͛͛ ··ζ·ϴνΊ̽Ί̯Σ͛ν ν̯ζΜ͋͛͛ Ϊι ̯ νϢ̼νχ̯ΣχΊ̯ΜΜϴ νΊΊΜ̯ι statement and the contents of the package do not exceed 8 grams. **FΪι νΪΜΊ͇ Ϊι̯Μ ͇Ϊν̯ͽ͋ ͕Ϊιν CDE· ζΪΜΊ̽ϴ ζιΪϭΊ͇͋ν ͕Ϊι ͋ϳ̽ΜϢνΊΪΣ Ϊ͕ ͞Ϊι̯Μ͟ ͕ιΪ χ·͋ ̽ΪΣχ̯ΊΣ͋ι Μ̯̼͋Μ

(b) (4)

Top Left


(b) (4)

Bottom Left

Dose 1 Dose 2 Remember to fill your prescription!

Bottom Right

Nabriva Therapeutics [Logo] Manufactured for Nabriva Therapeutics US, Inc. King of Prussia, PA 19406 © Nabriva Revised

Remember to fill your prescription! Dose 1 Dose 2

(b) (4)

(b) (4)

Bar Code LOT EXP

Top Right

NDC 72000-110-02 2 Tablets Rx only TRADENAME

(b) (4) tablets 600 mg

(Individual Unit Not For Sale)

(b) (4)

(b) (4)

Spine

1 Page of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page


(b) (4)

(b) (4)

(b) (4)

Item Comments on the Information Provided

in NDA Conclusions

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

TRADENAME tablets

Change to: TRADENAME (lefamulin) tablets

Strength (21CFR 201.10(d)(1); 21.CFR 201.100(b)(4)) and salt equivalency statement (space permitting)

600 mg Change to: 600 mg Add to top left panel: Each tablet contains 671 mg lefamulin acetate equivalent to 600 mg lefamulin

Route of administration 21.CFR 201.100(b)(3))

None Not required because it is oral

Net contents* (21 CFR 201.51(a))

2 Tablets Adequate

Name of all inactive ingredients (; Quantitative ingredient information is required for injectables) 21CFR 201.100(b)(5)**

Not present Should be added to top left panel

Lot number per 21 CFR 201.18

Present Adequate

Expiration date per 21 CFR 201.17

Present Adequate

͞·ϳ ΪΣΜϴ͟ νχ̯χ͋͋Σχ ζ͋ι 21 CFR 201.100(b)(1)

Present Adequate

Storage (not required)

Store at 20°C to 25°C (68°F to 77°F); excursions

Adequate

NDC number (per 21 CFR 201.2) (requested, but not required for all labels or labeling), also see 21 CFR 207.35(b)(3)

NDC 72000-110-02 Adequate

Bar Code per 21 CFR 201.25(c)(2)***

Present Adequate

Name of manufacturer/distributor (21 CFR 201.1)

Manufactured for Nabriva Therapeutics US, Inc. King of Prussia, PA 19406 © Nabriva

Adequate

Others DOSAGE and ADMINISTRATION: Take one tablet by mouth. every 12 hours. KEEP OUT OF REACH OF

Adequate. This package is not

child resistant (Amendment of

5/8/19). This package is not

mentioned in the ΄͜ ̼̯͋̽Ϣν͋ Ίχ͛ν


(b) (4)

CHILDREN.

Dose 1 Dose 2 Remember to fill your prescription!

(Individual Unit Not For Sale)

not for sale. Having the blister

pack be non-child resistant

appears to be acceptable but it

ν·ΪϢΜ͇ ̼͋ ̯ιΙ͇͋ ͞Α·Ίν ΄̯̽Ι̯ͽ͋

for Households Without Young

C·ΊΜ͇ι͋Σ͟ ΊΣ ̽ΪζΜΊ̯Σ̽͋ ϮΊχ· 16

CFR 1700.5 (a) (1) but it could be

͞΄̯̽Ι̯ͽ͋ ͲΪχ C·ΊΜ͇-·͋νΊνχ̯Σχ͟ Ί͕

the package is too small (16 CFR

1700.5 (b)). 21 CFR 201.10 (i)

which allows for omitting a

warning if the package is too small

does not seem applicable.

Recommend that we send the

͕ΪΜΜΪϮΊΣͽ χΪ χ·͋ ̯ζζΜΊ̯̽Σχ΄ ͞΄Μ̯͋ν͋

̯͇͇ ͞΄̯̽Ι̯ͽ͋ ͲΪχ C·ΊΜ͇-·͋νΊνχ̯Σχ͟

to the blister presentation in

accord with 16 CFR 1700. This

could go below the statement

ͩ͞EE΄ ΕΑ F ·E!CH F

CHͫ͜D·EͲ͟΅͟

*21 CFR 201.51(h) A drug shall be exempt from compliance with the net quantity declaration required by this section if Ίχ Ίν ̯Σ ΪΊΣχ͋Σχ Μ̯̼͋Μ͇͋ ··ν̯ζΜ͋͛͛ ··ζ·ϴνΊ̽Ί̯Σ͛ν ν̯ζΜ͋͛͛ Ϊι ̯ νϢ̼νχ̯ΣχΊ̯ΜΜϴ νΊΊΜ̯ι statement and the contents of the package do not exceed 8 grams. **FΪι νΪΜΊ͇ Ϊι̯Μ ͇Ϊν̯ͽ͋ ͕Ϊιν CDE· ζΪΜΊ̽ϴ ζιΪϭΊ͇͋ν ͕Ϊι ͋ϳ̽ΜϢνΊΪΣ Ϊ͕ ͞Ϊι̯Μ͟ ͕ιΪ χ·͋ ̽ΪΣχ̯ΊΣ͋ι Μ̯̼͋Μ

(b) (4)


5 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page

George Digitally signed by George Lunn Date: 5/16/2019 07:04:54PMLunn GUID: 508da72000029f40833369b0a181e8b3



NDA 211672 Lefamulin Tablets and NDA 211673 Lefamulin Injection

Review of Common Technical Document-Quality (Ctd-Q) Module 1

Labeling & Package Insert

Note: There is a common package insert for the tablets and the injection. This is reviewed

below. See separate reviews for the container and carton labels. The changes indicated

below have been conveyed to DAIP and added to the Share Point label.

1. Package Insert

(a) “Highlights” Section (21CFR 201.57(a))

-----------------------DOSAGE FORMS AND STRENGTHS--------------------

Item Information Provided in NDA

Reviewer’s !ssessment

Product title, Drug name (201.57(a)(2))

Proprietary name and established name

TRADENAME (lefamulin) injection,

TRADENAME (lefamulin)tablets

Dosage form, route of administration

For intravenous use For oral use

Adequate

Controlled drug substance symbol (if applicable)

NA

Dosage Forms and Strengths (201.57(a)(8))

A concise summary of dosage forms and strengths and salt equivalency statement

See above 150 mg of lefamulin

600 mg of lefamulin

(b) (4)

(b) (4)

(b) “Full Prescribing Information” Section

#2: Section 2 Dosage and Administration (21 CFR 201.57(c)(12))


2.3 Administration Instructions TRADENAME

(b) (4)Injection

(b) (4)

TRADENAME Tablets (b) (4)

If a dose is missed, the patient should take the dose as soon as possible and anytime up to 8 hours

prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, do

not take the missed dose, and resume dosing at the next scheduled dose.

Item Information Provided in NDA Reviewer’s Assessment

Special instructions for product

preparation (e.g.,

reconstitution, mixing with

food, diluting with compatible

diluents)

(b) (4) Need more specific

instructions but defer

to clinical

# 3: Dosage Forms and Strengths (21CFR 201.57(c)(4))

TRADENAME (b) (4)

Injection

Clear, colorless solution in a single-dose clear glass vial. Each vial contains 150 mg of lefamulin

in 15 mL of 0.9% sodium chloride. (b) (4)

TRADENAME Tablets

Blue, oval, coated tablet with ‘LEF 600’ printed in black on one side. Each tablet contains 600

mg of lefamulin.


(b) (4)

Item Information Provided in NDA Reviewer’s !ssessment

Available dosage forms Clear, colorless solution in a

single-dose clear glass vial

Blue, oval, coated tablet with

‘LEF 600’ printed in black on

one side

Adequate. Change to film-coated

Strengths: in metric system and salt equivalency statement

Each vial contains 150 mg of

lefamulin in 15 mL of

0.9% sodium chloride.

Each tablet contains 600 mg

of lefamulin

Recommend:

Each vial contains 150

mg of lefamulin in 15 mL

of

0.9% sodium chloride.

Each tablet contains 600

mg of lefamulin

A description of the identifying characteristics of the dosage forms, including shape, color, coating, scoring, and imprinting, when applicable. Include “functional score”, if present.

Clear, colorless solution in a

single-dose clear glass vial

Blue, oval, coated tablet with

‘LEF 600’ printed in black on

one side

Adequate

#11: Description (21CFR 201.57(c)(12))

TRADENAME is a semi-synthetic antibacterial agent for oral and intravenous administration.

TRADENAME, a pleuromutilin derivative, is available as 14-O-{[(1R,2R,4R)-4-Amino-2

hydroxycyclohexylsulfanyl]-acetyl}-mutilin (b) (4) . It is a chemical substance with a molecular

weight of 579.79 g/mol.

Its empirical formula is C30H49NO7S and its chemical structure is:


TRADENAME

TRADENAME . The inactive ingredients

tablets are available as blue, oval, coated tablets containing (b) (4)

(b) (4)

are mannitol, povidone K30, microcrystalline cellulose, croscarmellose sodium, talc, colloidal

silicon dioxide, magnesium stearate, (b) (4)

TRADENAME supplied as an injection concentrate for intravenous use is available in a glass

vial (b) (4)

The diluent is a clear, colorless solution. The inactive ingredients are citric acid anhydrous,

trisodium citrate dihydrate, sodium chloride, and water for injection.


(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)


Proprietary name and established name

(b) (4)Recommend:

TRADENAME

injection

supplied as a sterile

injection for

intravenous use

Dosage form and route of administration

for intravenous

use

Tablets

Adequate

Active moiety expression of Tablets…containing Recommend: strength with equivalence Tablets…containing statement for salt (if applicable)

(b) (4)

(b) (4)

671 mg

equivalent to 600 mg of

lefamulin

TRADENAME injection supplied as a sterile injection for intravenous use is available as a clear colorless solution in a glass vial containing 168 mg of lefamulin acetate equivalent to 150 mg of lefamulin in 15 mL of 0.9% sodium chloride

Inactive ingredient information (quantitative, if injectables 21CFR201.100(b)(5)(iii)), listed by USP/NF names.

The inactive ingredients are

mannitol, povidone K30,

microcrystalline cellulose,

croscarmellose sodium, talc,

colloidal silicon dioxide,

magnesium stearate,

place them in alphabetical order.

Injection formulation is adequate.

The inactive ingredients are

sodium chloride and

water for injection


Statement of being sterile (if applicable)

Not present Add statement

Pharmacological/ therapeutic class semi-synthetic antibacterial

agent

Adequate

Chemical name, structural formula, molecular weight

Present Adequate

If radioactive, statement of important nuclear characteristics.

NA

Other important chemical or physical properties (such as pKa, solubility, or pH)

The infusion bag is pH 5 Adequate

#16: How Supplied/Storage and Handling (21CFR 201.57(c)(17))

TRADENAME is supplied in the following strengths and package configurations:

TRADENAME (b) (4)

Injection

TRADENAME (b) (4) injection is a clear, colorless, sterile, nonpyrogenic solution

for intravenous administration containing 150 mg of lefamulin in 15 mL 0.9% sodium chloride

in a single (b) (4) vial intended for dilution in 250 mL of 10 mM citrate buffered (pH 5) 0.9%

sodium chloride. The drug product is provided in a clear type I glass 15 mL vial with a gray

rubber stopper, aluminum seal and (b) (4) flip off cap. The diluent is provided in

infusion bags containing 250 mL of sterile, nonpyrogenic 10mM citrate buffered (pH 5) 0.9%

sodium chloride solution.

They are supplied as follows:

150 mg single dose lefamulin vials (NDC 72000-120-06); packed in cartons of 6.

250 mL citrate buffer diluent bags (NDC 72000-030-06); packed in cartons of 6.

Storage and Handling (b) (4)

TRADENAME Injection should be stored at 2°C to 8°C (36°F to 46°F). Store in a

refrigerator. Do not freeze. The diluent bags should be stored at 20°C to 25°C (68°F to 77°F);

excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room

Temperature].

(b) (4)

TRADENAME Tablets

TRADENAME tablets are available as blue, oval, coated tablets containing

lefamulin

(b) (4)

(b) (4) The tablet is printed with ‘LEF 600’ in black

on one side.


They are supplied as follows: HDPE bottles of 30 tablets with Child-resistant Closure (NDC 72000-110-30)

(b) (4)

Storage and Handling

TRADENAME tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to

15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].


(b) (4)

(b) (4)

(b) (4)(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)


Strength of dosage form 150 mg of lefamulin in 15 mL

0.9% sodium chloride

tablets containing

600 mg

lefamulin.

Lefamulin/lefamulin acetate is used in an inconsistent manner

Suggest

tablets containing

600

mg lefamulin Available units (e.g., bottles of 100 tablets). Include child-resistant closure, induction seal, coil, and desiccant as appropriate.

150 mg of lefamulin in 15 mL

0.9% sodium chloride in a

single vial intended for

dilution in 250 mL of 10 mM

citrate buffered (pH 5) 0.9%

sodium chloride. The drug

product is provided in a

clear type I glass 15 mL vial

with a gray rubber stopper,

aluminum seal and

flip off cap.

The diluent is provided in

infusion bags containing 250

mL of sterile, nonpyrogenic

10mM citrate buffered (pH

5) 0.9% sodium chloride

solution.


HDPE bottles of 30 tablets

with Child-resistant Closure

(NDC 72000-110-30)

Suggest:

150 mg of lefamulin in 15

mL 0.9% sodium

chloride in a single-dose

vial intended for

dilution in 250 mL of 10

mM citrate buffered (pH

5) 0.9% sodium chloride.

The drug product is

provided in a

clear type I glass 15 mL

vial with a gray rubber

stopper, aluminum seal

and

flip off cap.

The diluent is provided in

infusion bags containing

250 mL of sterile,

nonpyrogenic 10mM

citrate buffered (pH

5) 0.9% sodium chloride

solution.

) Identification of dosage forms, e.g., shape, color, coating, scoring, imprinting, NDC number. Include “functional score”, if present.


150 mg single dose lefamulin

vials (NDC 72000-120-06);

packed in cartons of 6.

250 mL citrate buffer diluent

bags (NDC 72000-030-06);

packed in cartons of 6.

TRADENAME

tablets are available as

blue, oval, coated tablets

containing

600 mg

Suggest

TRADENAME

tablets

are available as blue, oval,

film-coated tablets

containing

600

mg lefamulin. The tablets

are printed with ‘LEF

600’ in black on one side.


(b) (4)

(b) (4)

lefamulin. The tablet is printed

with ‘LEF 600’ in black on

one side. Special handling (e.g., protect from light, do not freeze)

Store in a refrigerator. Do not

freeze.

Adequate

Storage conditions Storage and Ha ng

TRADENAME Injection

should be stored at 2°C to 8°C

(36°F to 46°F). Store in a

refrigerator. Do not

freeze. The diluent bags

should be stored at 20°C to

25°C (68°F to 77°F);

excursions permitted between

15°C and 30°C (59°F and

86°F) [See USP Controlled

Room Temperature].

Adequate. in-use stability has been verified from the CMC point of view (see section P.8). See also Quality Micro review.

Storage and Handling

TRADENAME tablets should

be stored at 20°C to 25°C

(68°F to 77°F); excursions

permitted to 15°C to 30°C

(59°F to 86°F) [see USP

Controlled Room

Temperature].

Manufacturer/distributor name listed at the end of PI, following Section #17

(b) (4)

TRADENAME is a trademark of Nabriva Therapeutics Ireland DAC


(b) (4)


Manufacturer/distributor name (21 CFR 201.1)

See above Adequate


George Digitally signed by George Lunn Date: 5/16/2019 07:05:27PMLunn GUID: 508da72000029f40833369b0a181e8b3



QUALITY ASSESSMENT

ATTACHMENT I: Final Risk Assessments


A. Final Risk Assessment - NDA

a) Drug Product

From Initial Risk Identification Review Assessment

Attribute/

CQA

Factors that

can impact the

CQA

Initial Risk

Ranking

Risk

Mitigation

Approach

Final Risk

Evaluation

Lifecycle

Considerations/

Comments

Assay,

stability

Formulation,

raw materials,

process

parameter,

scale/equipment

site

L Acceptable

Physical

stability

Formulation,

process

parameter

L The drug

substance

manufacturin

g process

Acceptable

Content

uniformity

Formulation,

raw materials,

process

parameter

L Acceptable

Microbial

limits

Formulation,

raw materials

L Microbial

limits

included in

Acceptable

(b) (4)



QUALITY ASSESSMENT

drug product

specification

Dissolution Formulation,

raw materials,

process

parameter

L The

dissolution

method and

acceptance

criteria were

found

acceptable in

the

biopharmaceu

tics review

Acceptable



Erika Digitally signed by Erika Englund Date: 5/17/2019 09:08:51AMEnglund GUID: 51389ea30003450414230afb8c3e8114


Erika Digitally signed by Erika Englund Date: 5/17/2019 11:27:22AMEnglund GUID: 51389ea30003450414230afb8c3e8114


21 Page(s) have been Withheld in Full as B4 (CCI/TS) immediately following this page

QUALITY ASSESSMENT

BIOPHARMACEUTICS

Product Background:

NDA: 211672

Drug Product Name / Strength: Lefamulin Tablet / 600 mg (base)

Route of Administration: Oral

Proposed Dosage (for the treatment of community-acquired bacterial pneumonia,

following treatment with Lefamulin for Injection 150 mg every 12 hours by IV

infusion): 600 mg orally every 12 hours for 5 days or at the

discretion of the physician. Swallow tablets whole (do not crush or divide).

Applicant Name: Nabriva

Primary Biopharmaceutics Reviewer: Gerlie Gieser, Ph.D.

Secondary Biopharmaceutics Reviewer: Elsbeth Chikhale, Ph.D.

Review Recommendation: APPROVAL

Review Summary:

The proposed dissolution method and acceptance criterion (as tabulated below) are approved for the routine QC of the proposed drug product at batch release and during

stability testing.

USP

Apparatus Speed Medium Volume Acceptance criterion

2 (paddle) 50 rpm 0.1N HCl,

37 ± 0.5°C 1000 mL Q = % (Q) at 60 min

The Phase 3 clinical trial lots and the final commercial image tablets have similar in vitro dissolution profiles, and thus are adequately bridged.

Biowaiver was not requested nor is required.

Over-encapsulation of Avelox and Zyvox tablets (to accomplish blinding of the Phase 3 clinical trials) did not impact that in vitro dissolution profiles of the tablets.

(b) (4)

(b) (4)



QUALITY ASSESSMENT

List of Submissions reviewed:

SDN-1, 12/19/2018 (Original NDA) SDN-7, 2/7/2019 (Response to Quality Information Request)

Concise Description of Outstanding Issues Remaining:

None

BCS Designation

There is no formal BCS Designation Request for the proposed oral tablet although the

Applicant considers lefamulin acetate as a BCS

drug substance.


Solubility: High. The solubility of lefamulin acetate is ≥ 100 mg/mL in 0.1 N HCl and

300 mM phosphate buffers at pH 6.8 and pH 7.4, and >300 mg/mL in water and 0.9%

sodium chloride solution. The Applicant indicated that the solubility of the drug

substance is high (>100 mg/mL) across the physiologic pH range, regardless of API

polymorphic form ; see Table 6 of SDN-7. Per the proposed labeling of

lefamulin tablet, the maximum recommended single dose is 600 mg (as lefamulin

base).

Permeability: Low. The absolute bioavailability of the oral tablet under fasted

conditions was ~25%; under fed conditions, 21% (see page 9 of the proposed labeling).

Dissolution: Not Rapid or Very Rapid. Per the Applicant, the dissolution of the tablets

is an erosion-controlled process. Using USP Apparatus 2 (paddle) rotating at 50 rpm,

and 1000 mL of various pH buffer media, less than % of the label claim of lefamulin

dissolves within minutes (see Figure 3 below).

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Dissolution Method and Acceptance Criterion


Dissolution Method – ADEQUATE

Justification for Chosen Method Parameters

Acidic medium (0.1N HCl) was chosen to simulate physiologic conditions of dissolution in the

stomach, in addition to achieving sink conditions during routine QC dissolution testing. The

relatively low paddle speed (50 rpm) was selected to maximize the dissolution method’s

discriminating power.



QUALITY ASSESSMENT

Discriminating Power

Overall, the provided data demonstrated that the proposed QC dissolution method has adequate

discriminating power for changes in the critical quality attributes of the drug product.

Specifically, the proposed QC dissolution method was demonstrated to be capable of detecting

intentional changes in the levels of the excipient, i.e., the (Povidone K90),

(croscarmellose sodium), and (magnesium stearate); see Figure 1. The comparative in

(b) (4) (b) (4)

(b) (4)

vitro dissolution profile data in Figure 1 provide direct evidence that the proposed dissolution

method is capable of rejecting drug products with quality attributes that could result in

unacceptably low dissolution rates.

Fig hes

(b) (4)

Source: Figure 11 of the Pharmaceutical Development Report (PDR).

See Table 12 of the PDR for the compositions of the variant drug product batches.

Additionally, the proposed QC dissolution method was able to detect the slightly faster

dissolution rate of the registration lots (see Figure 3 below). The Applicant pointed out that

compared to the Phase 3 clinical lots, the manufacture of the registration lots used a slightly

which resulted in the slight reduction in the registration lots’

and consequently, the requirement to .

(b) (4)

(b) (4) (b) (4)

[Notes: API particle size distribution (PSD) differences within the studied ranges (d10: μm,

d50: μm, d90: μm) were not shown to impact dissolution profile (Table 10/Figure

9 of 3.2.P.2 PDR), likely because the drug substance is highly soluble (per BCS criteria). Both

API were reported to be highly soluble. Disintegration (NMT min),

and (NMT %) are part of the finished product QC specifications.]

(b) (4)

(b) (4) (b) (4)

(b) (4)(b) (4)

(b) (4) (b) (4)

Stability-Indicating Potential

The proposed QC dissolution method has stability indicating potential as shown by the

significant reduction in the dissolution (and disintegration, with a slight increase in uptake)

of the tablets stored in under accelerated conditions ( ), but not

(b) (4)

(b) (4) (b) (4)



QUALITY ASSESSMENT

those stored under 25°C/60%RH conditions. [Based on the study findings, HDPE bottles and

blisters were chosen as the commercial packaging configurations of the proposed drug (b) (4)

product; see Figures 13 to 15 of the PDR.]

[Additionally, based on the and dissolution profiles of Registration Batch

W038336 during , this Reviewer considers reasonable (but defers

to the Drug Product Reviewer the final determination regarding the acceptability of) the proposed

limit of NMT %; see Table 5 of the 2/7/2019 Response to FDA Quality Comment

#2 dated 1/25/2019 (SDN-7), and Figure 12 of the PDR.]

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Analytical Method Validation

The drug in the dissolution sample is quantified using reversed-phase isocratic HPLC method

with UV detection at nm. The analytical method was validated for specificity, linearity, (b) (4)

accuracy, precision, robustness (in terms of HPLC and dissolution parameters including paddle

speed (± 5 rpm), medium temperature (± 5º C). The standard and the samples solutions were

reported to be stable for up to at room temperature and refrigerated conditions. Per the (b) (4)

Drug Product Reviewer (Dr. George Lunn), the analytical methods validation including that for

dissolution testing is adequate.

Dissolution Acceptance Criterion – ACCEPTABLE

Per the Applicant, the proposed dissolution acceptance criterion (Q = % at 60 min) was based

on the mean dissolution profile data (default Stage 2 testing) of the Phase 3 clinical trial lots at

(b) (4)

batch release and during stability testing.

Based on the dissolution profile data of the Phase 3 clinical trial lots at batch release and during

24 to 36 months of long-term (25 °C/60% RH) storage, this Reviewer considers reasonable the

proposed QC dissolution acceptance criterion (Q = % at 60 min). Additionally, based on

studies involving drug product batches with quantitative alterations in the level of excipients (as

depicted in Figure 11), ‘Q = % at 60 min’ is sufficient to reject tablet batches with substantially

low levels of the disintegrant and high levels of the lubricant.

(b) (4)

(b) (4)

REVIEWER NOTE: Recently, FDA had determined that it was not necessary to establish

discriminating power for drug products containing highly soluble drug substances, and that the

standard dissolution method(s) as prescribed in the 2018 FDA Guidance on Dissolution Testing

of Immediate Release Drug Products Containing High Solubility Drug Substances can be used.

Since the Applicant’s proposed dissolution method possess discriminating power and stability

indicating potential, and it (along with the appropriate acceptance criterion) does not preclude the

pivotal Phase 3 clinical trial lots from achieving complete dissolution/drug release, this Reviewer

believes that it is not necessary to recommend optimization (e.g., of the dissolution medium

volume) of the proposed QC dissolution method. Additionally, this Reviewer believes that it is

justified to accept the proposed specification time point of 60 min (instead of the Guidance

recommended specification time point of min to achieve a Q of %) for the QC dissolution

acceptance criterion because it represents the start of the dissolution plateau, and is associated

with lower data variability than the earlier dissolution sampling time points, as evidenced by the

(b) (4)

(b) (4)



QUALITY ASSESSMENT

dissolution profile data of the Phase 3 clinical trial lots at batch release and during long-term

storage.

Dissolution on Stability

As shown in Figure 2, there were no apparent trends in the dissolution profiles of the two Phase 3

clinical trial lots during long-term storage, regardless of the primary packaging configuration

blister or HDPE bottles).

The Applicant reported that all stability batches conformed to the proposed dissolution

acceptance criterion, i.e., including the Phase 3 clinical trial lots and the three registration lots

under long-term storage for up to 36 months and up to 12 months, respectively.

Figure 2. Dissolution Profiles of the Pivotal Phase 3 Clinical Trial Lots During

24 months to 36 months of Long-Term Storage

(b) (4)

(b) (4)

Bridging of Formulations

Reviewer’s Assessment: ADEQUATE

The final proposed to-be-marketed tablet is the same as the Phase 3 clinical trial tablet in terms of

formulation composition, manufacturing process and drug product manufacturer ( ), as (b) (4)



QUALITY ASSESSMENT

well as the API manufacturer ( ), but not in terms of appearance (blue coating with black

imprint vs. yellow coating/unmarked). The registration and the clinical batch sizes are considered

similar kg versus kg, respectively).

Figure 3 shows that the in vitro dissolution profiles of the Phase 3 clinical trial tablets and the final

commercial image tablets (i.e., as represented by the validation and registration batches) in the

proposed QC dissolution medium and in various pH media are comparable, with calculated profile

similarity (f2) values >50.

That the registration stability lots have a slightly faster dissolution rate than the Phase 3 clinical trial

lots is not expected to pose a safety concern for the following reasons: (1) the drug substance

exhibits high solubility in media with pH across the physiologic range, (2) the drug product is an

immediate release oral tablet, and (3) a similar (Phase 1) immediate release lefamulin tablet

formulation with a faster dissolution rate was shown to be bioequivalent (in terms of plasma Cmax

and AUC) to the Phase 3 tablet; see Figure 1 of 2.7.1 Summary of Biopharmaceutics.

Figure 3. Comparative Dissolution Profiles of Pivotal Clinical Trial Lots and Registration Lots

in Various pH Media

Note that PK data for the earlier clinical (capsule and tablet) formulations are available should in

vivo BE bridging to the final tablet formulation be needed.

REVIEWER NOTE:

Regarding the active comparator tablets used in the double-blinded pivotal Phase 3 clinical trials:

The comparative in vitro dissolution profile data provided by the Applicant indicate that the